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Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AF-TIMI 48 trial
IJCA-28264; No of Pages 7 International Journal of Cardiology xxx (xxxx) xxx
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Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AF-TIMI 48 trial Anna Plitt a, Christian T. Ruff b, Assen Goudev c, Joao Morais d, Miodrag C. Ostojic e, Michael A. Grosso f,1, Hans J. Lanz g, Jeong-Gun Park b, Elliott M. Antman b, Eugene Braunwald b, Robert P. Giugliano b,⁎ a
Mount Sinai Heart, New York, NY, United States of America TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, United States of America UMHAT “Tzaritza Yoanna-ISUL” EAD Clinic of Cardiology, Sofia, Bulgaria d Santo Andre's Hospital, Cardiology Division, Leiria, Portugal e School of Medicine University of Belgrade, Belgrade, Serbia f Daiichi Sankyo Inc., Basking Ridge, NJ, United States of America g Daiichi Sankyo Europe GmbH, Munich, Germany b c
a r t i c l e
i n f o
Article history: Received 25 October 2019 Received in revised form 30 November 2019 Accepted 8 January 2020 Available online xxxx Keywords: Atrial fibrillation Diabetes mellitus Non-vitamin K antagonist oral anticoagulants Stroke prevention
a b s t r a c t Background: Diabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/ benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest. Methods: 21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624). Results: On average, patients with diabetes were younger, and had a higher body mass index, CHA2DS2-VASc score and baseline endogenous Factor Xa activity. After multivariate adjustments, patients with diabetes had a similar rate of stroke and systemic embolism compared to those without diabetes (adjusted hazard ratio (HRadj) 1.08; 95% confidence interval (CI) 0.94–1.24; p = 0.28). However, the risk of major bleeding was significantly higher in patients with diabetes (HRadj 1.28; 95% CI 1.14–1.44; p b 0.001). The treatment effect of edoxaban (vs warfarin) was not modified by diabetes (all p-interactions N 0.05), a finding supported by the preserved edoxaban concentrations and inhibition of Factor Xa regardless of diabetes. The HRs of stroke and systemic embolism in patients receiving the higher-dose edoxaban regimen vs warfarin were 0.93 and 0.84 (pinteraction = 0.54) in those with and without diabetes respectively. The higher-dose edoxaban regimen reduced major bleeding (by 19–21%) and cardiovascular death (by 7–17%) regardless of diabetes (p-interactions = 0.81 and 0.33 respectively). Conclusion: Patients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes. © 2020 Elsevier B.V. All rights reserved.
1. Introduction Atrial fibrillation (AF) and diabetes mellitus are chronic conditions and both are independently associated with an increased risk of stroke and death [1,2]. AF is the most common chronic cardiac arrhythmia in the United States and worldwide [3] and is associated with a 4- to 5fold increased risk of stroke [4]. Diabetes is associated with a 2-fold excess risk of stroke [5], and longer duration of diabetes is linked with
⁎ Corresponding author at: TIMI Study Group, Hale BTM, Suite 7022, 60 Fenwood Road, Brigham and Women's Hospital, Boston, MA 02115, United States of America. E-mail address: [email protected] (R.P. Giugliano). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
even higher ischemic stroke rates [6]. These two conditions share similar risk factors including age, hypertension, and obesity [7], and are increasing in prevalence with the aging of the population [8,9]. Thus, further research among patients with both AF and diabetes, particularly as newer therapies are introduced, are of clinical interest. Edoxaban is a once-daily oral direct factor Xa inhibitor that is approved for the prevention of stroke and systemic embolic events (SEE) in patients with AF. In this manuscript from the pivotal phase 3 Effective aNticoaGulation with factor Xa next GEneration in Atrial Fibrillation– Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF–TIMI 48) trial [10], we compare adjusted outcomes in patients with vs without diabetes, report the pharmacokinetic and pharmacodynamic results, and the relative efficacy and safety of edoxaban compared to warfarin in patients stratified by diabetes status.
https://doi.org/10.1016/j.ijcard.2020.01.009 0167-5273/© 2020 Elsevier B.V. All rights reserved.
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
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A. Plitt et al. / International Journal of Cardiology xxx (xxxx) xxx
2. Methods The design of the ENGAGE AF-TIMI 48 trial has been described previously [10,11]. In brief, this was a double-blind, double-dummy trial of 21,105 patients with AF at moderate-to-high risk of stroke randomized in 1:1:1 fashion to a higher-dose edoxaban regimen (HDER, 60 mg once daily), lower-dose edoxaban regimen (LDER, 30 mg once daily), or warfarin titrated to a target international normalized ratio (INR) of 2.0–3.0. A dose reduction of edoxaban by 50% in both edoxaban arms was mandated for any of the following: estimated creatinine clearance (CrCl) ≤ 50 mL/min using the Cockroft-Gault equation [12], weight ≤ 60 kg, or concomitant use of strong P-gp inhibitors. The primary efficacy endpoint was a composite of all stroke or SEE, and the principal safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Hemostasis (ISTH) [13]. Key secondary endpoints included cardiovascular death, stroke or SEE; major adverse cardiac events (MACE = MI, stroke, SEE, or death due to cardiovascular cause or bleeding); and the composite of all-cause death, stroke or SEE. Three net outcomes combing efficacy, safety, and mortality endpoints were analyzed: Primary = stroke, SEE, major bleeding, or death; Secondary = disabling stroke, life-threatening bleeding, or death; Tertiary = stroke, SEE, life-threatening bleeding, or death. The data were analyzed by pre-specified categories of diabetes (yes/ no) at randomization as determined by the local investigator. The subgroup of patients with diabetes was further stratified into non-insulin treated and insulin-treated diabetes. We hypothesized that the safety and efficacy of edoxaban would be preserved across subgroups stratified by diabetes status. Baseline characteristics were reported as percentages for categorical variables and were compared using the Chi-square test. Continuous variables were reported as medians with interquartile ranges and were compared using Wilcoxon rank-sum test or Kruskal-Wallis test of difference. Outcomes were presented as percentage of events per year and were compared using Cox proportional hazard models. Multivariate Cox regression models were used to adjust for baseline characteristics across the groups stratified by diabetes status. Covariates used for adjustment are shown in Table 1. The proportionality assumption was confirmed by assessment of Schoenfield residuals. There were no proportional hazards assumption violations for the study variables of history of diabetes and diabetes treatment status for the primary endpoints. Interactions between the randomized treatment and diabetes status were then tested by Cox proportional hazard modeling to address treatment-effect modification associated with diabetes. Differences between randomized treatment groups are presented as hazard ratios (HR) with 95% confidence intervals (CIs). HDER is the approved edoxaban regimen for stroke prevention in patients with AF, as the LDER was less effective than warfarin in preventing ischemic stroke. Therefore, we focused this analysis on the comparison of HDER vs warfarin and present data for the LDER in the Supplement. Endogenous FXa activity was measured at baseline and day 29 at peak and trough as previously described [14–16]. All analyses were performed using the SAS software, version 9.4 (SAS Institute Inc., Cary, NC). A 2-sided p b 0.05 was considered to indicate statistical significance, without adjustment for multiple comparisons. 3. Results Of the 21,105 patients who were enrolled in the ENGAGE AF-TIMI 48 trial, 7,624 (36%) had a history of diabetes (including 1,270 (6%) treated with insulin and 6,354 (30%) not receiving insulin) at randomization; 13,481 (64%) patients had no history of diabetes. Baseline characteristics differed by diabetes status (Table 1) but were similar by randomized treatment within each diabetes stratum (Supplementary Appendix Table S1). For example, patients with diabetes were on average
Table 1 Patient characteristics stratified by diabetes status. Characteristica Age (y), median (IQR) BMI (kg/m2), median (IQR) Weight (kg), median (IQR) Female Region North America Latin America Western Europe Eastern Europe Asia-Pacific and South Africa Prior stroke/TIA Congestive heart failure Hypertension Paroxysmal AF Prior VKA experienced Dose reduction at randomization CrCl (mL/min) ≤50 Weight ≤ 60 kg Use of verapamil/quinidine CHA2DS2VASc score Mean (SD) Median (IQR) N3 ≤3 CHA2DS2VASc score – without including diabetes in score Mean (SD) Median (IQR) N3 ≤3 Baseline laboratory studies Endogenous FXa activity (median, IQR) CrCl (mL/min), median (IQR) Platelet count (×103/μL) Hemoglobin (g/dL) NT-pro BNP (pg/mL) (median, IQR) hs-TNT (pg/mL) (median, IQR) GDF-15 (pg/mL) (median, IQR) Medication at time of randomization Aspirin Thienopyridine Amiodarone RAA inhibitor
Diabetes (N = 7,624)
No diabetes (N = 13,481)
70 (63, 76) 30.4 (26.9, 34.7) 87 (75, 102) 2782 (36.5)
73 (65, 78) 27.8 (24.8, 31.3) 79 (68, 91) 5258 (39.0)
2111 (27.7) 758 (9.9) 1242 (16.3) 2379 (31.2) 1134 (14.9) 1587 (20.8) 3681 (48.3) 7237 (94.9) 2014 (26.4) 4749 (62.3) 1491 (19.6) 1128 (14.8) 445 (5.8) 275 (3.6)
2570 (19.1) 1903 (14.1) 1994 (14.8) 4765 (35.3) 2249 (16.7) 4386 (32.5) 8443 (62.6) 12517 (92.8) 3352 (24.9) 7692 (57.1) 3865 (28.7) 2946 (21.9) 1638 (12.2) 486 (3.6)
4.6 (1.5) 5.0 (4.0–6.0) 5764 (75.6) 1860 (24.4)
4.2 (1.3) 4.0 (3.0–5.0) 9155 (67.9) 4326 (32.1)
3.6 (1.5) 4.0 (3.0–5.0) 3892 (51.0) 3732 (49.0)
4.2 (1.3) 4.0 (3.0–5.0) 9155 (67.9) 4326 (32.1)
N = 524 0.91 (0.80, 1.05) 76.6 (58.2–100.3) 196 (164–233) 13.9 (12.9–14.9) N = 3233 725 (350, 1306) N = 3214 14.6 (10.0, 21.9) N = 3214 1960 (1350, 2986)
N = 1037 0.88 (0.76, 1.01) 67.0 (52.0–86.9) 196 (164–231) 14.1 (13.1–15.1) N = 5509 865 (408, 1500) N= 5469 13.2 (9.4, 19.5) N = 5468 1529 (1111, 2162)
2400 (31.5) 205 (2.7) 797 (10.5) 5246 (68.8)
3780 (28.0) 282 (2.1) 1695 (12.6) 8660 (64.2)
AF, atrial fibrillation; CrCl, creatinine clearance; GDF-15, Growth Differentiation Factor-15; hs-TNT, high sensitivity cardiac troponin T; NT-proBNP, N-terminal pro b-type natriuretic peptide; RAA, rening, angiotensin, or aldosterone; TIA, transient ischemic attack; VKA, vitamin K antagonists. p b 0.001 for all comparisons except: p = 0.17 for Digoxin/Digitalis preperation use; p = 0.006 for thienopyridine use; p = 0.42 for platelet count. a Data shown are number (%) unless otherwise indicated. Data presented are median (interquartile ranges) for continuous variables and number (percentages) for categorical variables. Data for endogenous factor Xa activity are as a proportion of normal controls.
3 years younger (median 70 vs 73) and had a higher body mass index (BMIs) mean (31.3 vs 28.4 kg/m2) and CHA2DS2-VASc score (mean 4.6 vs 4.2) as compared to patients without diabetes (each p b 0.001). Excluding the 1 point for diabetes, the mean CHA2DS2-VASc score was 3.6 in patients with diabetes and 4.2 in those without diabetes (p b 0.001). This finding of an average of 0.6 more stroke risk factors other than diabetes in patients without diabetes likely was related to the minimum CHADS2 score of 2 that was required for participation in the trial (i.e., patients without diabetes had to have at least 2 of the other risk factors). The mean CHADS2 scores, excluding the point for diabetes, were 2.2 vs 2.7 (p b 0.001) for patients with and without diabetes. Among patients with diabetes, 20.8% had history of stroke/transient ischemic attack vs 32.5% of patients without diabetes (p b 0.001), and
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
A. Plitt et al. / International Journal of Cardiology xxx (xxxx) xxx
48.3% of patients with diabetes had history of congestive heart failure vs 62.6% without diabetes (p b 0.001). Patients with diabetes were less likely to meet edoxaban dose reduction criteria at randomization (19.6% vs 28.7%, p b 0.001), mostly driven by fewer patients having a creatinine clearance b 50 mL/min among patients with diabetes (14.8% vs 21.9%, p b 0.001). Among the 42% of patients participating in the biomarker substudy, patients with diabetes had higher median levels hs-TnT (14.6 vs 13.2 pg/mL) and GDF-15 (1960 vs 1529 pg/mL), but lower levels of NT-pro BNP (725 vs 865pg/mL) compared to patients without diabetes, p b 0.0001 for each of the 3 biomarkers (Table 1). Patients with diabetes had a higher median level of endogenous Factor Xa activity at baseline (0.91 vs 0.88, p = 0.0003) than those without diabetes. There were no statistically significant differences in the baseline characteristics between patients randomized to warfarin or edoxaban, either among patients with diabetes who were treated with or without insulin (Table S2).
3.1. Efficacy outcomes in patients by diabetes status The observed (unadjusted) rates of stroke/SEE in patients with and without diabetes were 1.61% vs 1.91%/year respectively, adjusted hazard ratio (HRadj was1.08, p = 0.28). After multivariate adjustment, the risk for several composite endpoints (including stroke, SEE, major bleeding, or death; disabling stroke, life-threatening bleeding, or death; and disabling stroke, SEE, life-threatening bleeding, or death) were significantly higher in patients with diabetes (Table 2). The adjusted risks of the primary and secondary efficacy endpoints were significantly higher among patients with diabetes treated with insulin compared to those without insulin-treated diabetes (Table S3). There was no difference in adjusted rates of stroke/SEE in patients with diabetes not receiving insulin vs patients without diabetes (HRadj 1.01; 95% CI 0.88–1.17; p = 0.85).
3.2. Safety outcomes in patients by diabetes status Major bleeding was significantly higher in patients with diabetes vs without diabetes (3.06%/year vs 2.57%/year, HRadj 1.28, p b 0.001) (Table 2). Similarly, the adjusted risks of major or CRNM bleeding (HR adj 1.10, p = 0.002) and all bleeding (HRadj 1.08, p = 0.008) also were significantly higher in patients with diabetes vs without diabetes. The higher rates of bleeding in patients with diabetes were driven by extracranial, non-fatal bleeding (2.59%/year vs 2.09%/year, HRadj 1.28, p b 0.001), since ICH (0.48%/year vs 0.49%/ year, HRadj 1.27, p = 0.09) and fatal bleeding (0.21%/year vs 0.25%/ year, HRadj 1.07, p = 0.73) were similar between the groups. Among patients with diabetes, the risk of major bleeding (Table S3) was highest in patients with diabetes treated with insulin (HR adj 1.31; 95% CI 1.05–1.61; p = 0.015).
3.3. Net outcomes in patients by diabetes status The annualized rate of the primary net outcome (composite of stroke, SEE, major bleed, or death) was increased in patients with diabetes as compared to patients without diabetes (7.65% vs 7.23%/year, HRadj 1.25, 95% CI 1.17–1.34, p b 0.001) (Table 2). A similar magnitude of increased adjusted risk in patients with diabetes was seen for the secondary (HRadj 1.26) and tertiary net outcomes (HRadj 1.27), both p b 0.001. Among patients with diabetes, the net outcomes were worst among patients treated with insulin (HRadj 1.57, 1.73 and 1.73 vs non-insulin treated diabetes for the 3 net outcomes, p b 0.0001 for each comparison, Table S3).
3
Table 2 Outcomes stratified by the presence of diabetes at randomization.
Efficacy endpoints Stroke/SEE Stroke Ischemic Hemorrhagic Nondisabling and nonfatal Disabling or fatal Fatal SEE Key secondary endpoints CV death, stroke or SEE MACE All-cause death, stroke or SEE All-cause mortality CV death Safety endpoints Major bleeding ICH Non-ICH Major or CRNM Fatal or life-threatening bleed Gastrointestinal bleeding All bleeding Net clinical outcomes Primary Secondary Tertiary
Diabetes (N = 7624) % patients/year
No diabetes (N = 13,481) % patients/year
Diabetes vs no diabetes HRadj (95%CI)
1.61 1.52 1.26 0.29 0.87
1.91 1.80 1.51 0.30 1.05
1.08 (0.94, 1.24) 1.07 (0.93, 1.23) 1.07 (0.92, 1.25) 1.11 (0.79, 1.54) 1.02 (0.85, 1.22)
0.70 0.39 0.10
0.77 0.43 0.13
1.19 (0.97, 1.48) 0.10 1.22 (0.92, 1.62) 0.16 1.09 (0.64, 1.87) 0.75
4.04 4.84 5.20
4.24 4.71 5.31
1.21 (1.11, 1.32) b0.001 1.28 (1.18, 1.38) b0.001 1.23 (1.14, 1.33) b0.001
4.09 2.87
4.02 2.87
1.30 (1.20, 1.42) b0.001 1.29 (1.17, 1.43) b0.001
3.06 0.48 2.59 11.6 0.73
2.57 0.49 2.09 10.5 0.72
1.28 (1.14, 1.44) 1.27 (0.96, 1.68) 1.28 (1.13, 1.46) 1.10 (1.04, 1.17) 1.20 (0.96, 1.50)
1.40
1.11
1.29 (1.08, 1.54) 0.004
14.8
13.4
1.08 (1.02, 1.14) 0.008
7.65 4.79 4.86
7.23 4.73 4.81
1.25 (117, 1.34) b0.001 1.26 (1.16, 1.37) b0.001 1.27 (1.17, 1.37) b0.001
p value
0.28 0.33 0.39 0.55 0.85
b0.001 0.09 b0.001 0.002 0.11
Adjusted hazard ratios and confidence intervals were derived from a Cox model adjusted for the following factors: age, body mass index (BMI), sex, Caucasian race, region, history of: stroke/transient ischemic attack (TIA), congestive heart failure, hypertension, paroxysmal atrial fibrillation, CrCl ≤ 50 mL/min at randomization, or use of: Vitamin K antagonist, strong P-gp inhibitor, aspirin, thienopyridine, amiodarone or digoxin/digitalis preparation at randomization. p values were calculated using the log rank test. CV, cardiovascular; CRNM, clinically relevant non-major; ICH, intracranial hemorrhage; MACE, MI, stroke, SEE, or death due to CV or bleeding; SEE, systemic embolic event. Primary net clinical endpoint is the composite of stroke, SEE, major bleeding, or death. Secondary net clinical endpoint is the composite of disabling stroke, life-threatening bleeding, or death. Tertiary endpoint is the composite of disabling stroke, SEE, life-threatening bleeding, or death.
3.4. Pharmacokinetics and pharmacodynamics 3.4.1. Edoxaban concentration and Factor Xa results at day 29 After stratification by the edoxaban dose received, the median trough concentrations of edoxaban, extrinsic anti-factor Xa activity at trough, and suppression of baseline endogenous factor Xa activity at peak and trough generally were similar in patients with diabetes as compared to those without diabetes (Table 3). In the HDER group that did not undergo dose reduction (i.e., patients who received 60 mg), there were significantly lower levels of edoxaban concentration (34.3 vs 37.2 ng/mL, p = 0.04) and suppression of endogenous factor Xa activity (−18% vs −24%, p = 0.0003) at trough in diabetics compared to non-diabetics, although these modest differences are of uncertain clinical significance.
3.4.2. International normalized ratio (INR) in the warfarin arm The median values for the time-in-therapeutic range (TTR) of the INR in the warfarin arm were similar among patients with diabetes vs without diabetes (68.6% vs 68.4%, p = 0.12), and in patients with diabetes who were treated with vs without insulin (68.2% vs 68.7%, p = 0.32)
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
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Table 3 Edoxaban concentration and anti-factor Xa results. Higher-dose edoxaban regimen Diabetes mellitus
No diabetes mellitus
Edoxaban patients who were not dose-reduced at randomization (HDER = 60 mg, LDER 996 Day 29 trough edoxaban concentration (ng/mL) N 34.3 Median (18.5, 60.8) IQR 439 Day 29 trough Anti-FXa activity (IU/mL) N 0.59 Median (0.33, 1.13) IQR 449 Day 29 peak endogenous FXa, % change from baseline N −67 Median IQR (−76, −52) 458 Day 29 trough endogenous FXa, % change from baseline N −18 Median (−30, −7) IQR
= 30 mg) 1507 37.2 (20.3, 62.8) 690 0.68 (0.39, 1.13) 738 −67 (−75, −52) 758 −24 (−34, −11)
Edoxaban patients who were dose-reduced at randomization (HDER = 30 mg, LDER = 15 mg) 562 259 Day 29 trough edoxaban concentration (ng/mL) N 26.3 28.7 Median (15.1, 43.1) (13.4, 48.4) IQR 223 91 Day 29 trough Anti-FXa activity (IU/mL) N 0.5 0.60 Median (0.3, 0.8) (0.30, 0.99) IQR 235 89 Day 29 peak endogenous FXa, % change from baseline N −58 −60 Median (−66, −44) (−67, −47) IQR 243 98 Day 29 trough endogenous FXa, % change from baseline N −18 −18 Median (−26, −7) (−28, −7) IQR
Lower-dose edoxaban regimen p value
0.04
0.11
0.66
0.0003
0.56
0.11
0.22
0.54
Diabetes mellitus
No diabetes mellitus
1021 17.7 (9.55, 31.6) 440 0.33 (0.20, 0.57) 478 −52 (−60, −35) 493 −11 (−20, −3)
1591 18.8 (10.3, 32.8) 662 0.36 (0.22, 0.58) 694 −50 (−60, −36) 723 −12 (−21, −5)
221 12.4 (7.13, 19.1) 75 0.27 (0.18, 0.47) 81 −36 (−47, −19) 86 −9 (−14, −3)
623 12.4 (7.51, 21.5) 235 0.27 (0.18, 0.43) 241 −39 (−45, −27) 251 −10 (−17, −3)
p value
0.14
0.21
0.43
0.09
0.24
0.57
0.56
0.46
Anti-FXa, anti-factor Xa; Diabetes Mellitus, diabetes mellitus; HDER, high dose edoxaban regimen; IQR, interquartile range; IU/mL, international units/mL; LDER, low dose edoxaban regimen; ng/mL, nanograms/mL.
(Table S4). Likewise, no differences were seen in the percentages of time with an INR b 2.0 or an INR N 3.0 in patients stratified by diabetes or among patients with diabetes treated with vs without insulin (Table S4). 3.5. Outcomes with high dose edoxaban vs warfarin 3.5.1. Efficacy endpoints There was no significant effect modification by diabetes status on the relative treatment effect of HDER as compared to warfarin for the primary endpoint of stroke or SEE (Fig. 1). Which is further illustrated by the Kaplan Meyer curves in Fig. S1 Panels A–B. Annualized rates of stroke or SEE in patients with diabetes randomized to HDER vs warfarin were 1.42% vs 1.52%/year (HR 0.93, 95% CI 0.71–1.23) and in patients without diabetes were 1.65% vs 1.96%/year (HR 0.84, 95% CI 0.70–1.02, p-interaction 0.54). Similarly, the reductions in composite and mortality endpoints with edoxaban were not modified by diabetes status (Fig. 1), even after further stratification by the presence or absence of dose reduction criteria (Tables S5A, S5B). 3.5.2. Safety and net outcomes HDER consistently reduced major bleeding compared to warfarin in patients with (3.20% vs 4.07%/year, HR 0.79, 95% CI 0.65–0.96) and without diabetes (2.68% vs 3.30%/year, HR 0.81, 95% CI 0.69–0.96, pinteraction 0.81; Fig. 1). Reductions in other bleeding endpoints and improved net outcomes with HDER compared to warfarin were similar in patients with vs without diabetes (Fig. 1). There were no significant effect modifications on safety endpoints or net outcomes with HDER vs warfarin when stratified by diabetes status in patients who were and were not dose reduced (Tables S5A and S5B). An analysis of the location of major bleeding events by treatment group showed similar patterns in patients with vs without diabetes, with lower rates in the edoxaban group in most locations, except for the gastrointestinal system which was increased with HDER (Tables S5A and S5B), but not with LDER, compared to warfarin.
3.6. Results by randomized treatment in patients with diabetes stratified by insulin use When the outcomes comparing HDER vs warfarin in patients with diabetes were analyzed and stratified by use of insulin, none of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification (Table S6), regardless of whether patients did not or did meet dose reduction criteria (Tables S7A and S7B). 3.7. Lower-dose edoxaban regimen There were no significant effect modifications by diabetes status on the relative treatment effect of LDER vs warfarin for efficacy, safety, or net outcomes (Fig. S2). 4. Discussion In this analysis of patients with AF stratified by diabetes status from a large randomized controlled trial of patients at moderate to high risk of stroke, we found that: 1) After adjustment for baseline characteristics, there was no significant difference in rates of stroke/SEE between patients with vs without diabetes, 2) Patients with diabetes had significantly higher adjusted risks of bleeding and death, particularly those treated with insulin, 3) The efficacy and safety profiles of edoxaban compared to warfarin were similar regardless of diabetes status. The similar pharmacokinetic (edoxaban concentrations) and pharmacodynamic (anti-factor Xa measures with edoxaban, INR with warfarin) results stratified by diabetes status help to explain the similar efficacy and safety profile of edoxaban relative to warfarin regardless of the presence or absence of diabetes. 4.1. Comparison with other studies of NOACs in AF Given the differences in the patient populations, dosing regimens, definitions of endpoints (particularly bleeding events), and methods
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
A. Plitt et al. / International Journal of Cardiology xxx (xxxx) xxx
<-- Better in Edoxaban Group
5
Worse in Edoxaban Group-->
Fig. 1. Key Outcomes by Treatment and Diabetes status. The rates of stroke and systemic embolic events, major bleeding and selected composite outcomes are shown, comparing the higher dose edoxaban regimen (HDER) with warfarin. CV, cardiovascular; MACE, MI, stroke, SEE, or death due to CV or bleeding; Primary net clinical outcome is composite of stroke, SEE, major bleeding, or death; SEE, systemic embolic event. 1p-interaction, interaction effect between history of diabetes and study treatment group (warfarin & high-dose edoxaban). Hazard ratios for higher-dose edoxaban regimen vs warfarin are shown in blue for patient with diabetes and in red for patients without diabetes. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
of analyzing patients with diabetes, it is challenging to compare results across the trials and registries of NOACs in patients with AF in the absence of direct comparisons. In the RE-LY trial, statistically significantly higher adjusted rates of stroke or SEE and major bleeding were reported in patients with diabetes compared to patients without diabetes [17]. In the ROCKET-AF trial, the observed (unadjusted) rates of stroke/SEE and major bleeding were similar in patients with vs without diabetes [18]. Post marketing data suggested increased rates of major bleeding in a diabetes cohort of 44,793 patients with AF treated with rivaroxaban as compared to those without diabetes [19]. In the ARISTOTLE trial, the adjusted rates of stroke/SEE were also similar in patients with and without diabetes, while bleeding rates were higher in patients with diabetes [20]. Furthermore, an adjusted analysis from the PREFER in AF (European Prevention of thromboembolic events-European Registry in Atrial Fibrillation) registry showed that among 1288 patients with diabetes, the 288 patients treated with insulin were at the highest risk of thromboembolism [21]. In a recent meta-analysis, the use of NOACs vs warfarin was noted to be associated with lower risk of stroke/SEE in patients with diabetes (Risk Ratio [RR] 0.80, 95% CI 0.68–0.93; p = 0.004) as well as lower risk of vascular death (4.97% vs 5.99%; RR 0.83, 95% CI 0.72–0.96; p = 0.01) [22]. Similar to our findings with edoxaban, there were no significant effect modifications due to diabetes on the efficacy and safety profiles of either dabigatran or rivaroxaban relative to warfarin in the RE-LY [17] or ROCKET-AF [18] trials, respectively. In the ARISTOTLE trial [20], the efficacy of apixaban was maintained in both the presence and absence of diabetes. However, while the rate of ISTH major bleeding in patients without diabetes was significantly reduced with apixaban relative to
warfarin (HR 0.60, 95% CI [0.51–0.72]), major bleeding rates with apixaban vs warfarin were similar in patients with diabetes (HR 0.96, 95% CI [0.74–1.25], p-interaction 0.003). A similar significant treatment interaction with diabetes was seen for the endpoint of major or clinically-relevant nonmajor bleeding (p b 0.001). Of note, patients with diabetes in ARISTOTLE had significantly higher rates of gastrointestinal (HR 1.50 95% CI (1.16–1.95)) and intraocular bleeding (HR 1.90 95% CI (1.06–3.42)) than patients without diabetes in ARISTOTLE. Further evaluation of bleeding with apixaban in patients with diabetes is needed to establish whether these observations in ARISTOTLE were due to the play of chance or represent a reduction in the safety margin of apixaban relative to warfarin in patients with diabetes. Thus edoxaban is the only NOAC shown to significantly reduce major bleeding in patients with diabetes mellitus. 4.2. Limitations These observations are derived from a clinical trial that enrolled patients with CHADS2 risk score of 2 or greater, all of whom were treated with an oral anticoagulant, and thus may not apply to the general population of patients with AF and diabetes seen in clinical practice. The trial entry criteria required a minimum CHADS2 score of 2, thus patients with diabetes tended to have relatively fewer of the other stroke risk factors as compared to patients without diabetes, since the presence of diabetes counted for 1 point towards the 2-point minimum. This may have partially mitigated the risk associated with diabetes in our dataset compared to that reported in unselected observational studies and trials with no minimum risk score. We acknowledge that despite
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
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the large sample size of the trial, the study was not powered for subgroup analyses. The presence of diabetes and treatments were determined at randomization and may have changed during the trial. We did not collect data on the duration or type of diabetes mellitus, nor were therapies for diabetes or their duration systematically reported after randomization. We also did not collect the quality of diabetes control during the trial. 5. Conclusion In the ENGAGE AF-TIMI 48 trial of patients with AF treated with oral anticoagulation, the adjusted rates of bleeding and mortality are higher in patients with diabetes as compared to those without diabetes. The efficacy (protection from stroke/SEE, reduction in cardiovascular mortality) and safety (reduction in bleeding, particularly ICH) profiles of edoxaban relative to warfarin were not modified by the presence of diabetes. Edoxaban concentration and anti-factor Xa effects were similar in patients with vs without diabetes. These consistent clinical and laboratory results make the higher dose edoxaban regimen an attractive alternative to warfarin in patients with or without diabetes. Since patients with insulin treated diabetes and AF are at higher risk for both stroke and bleeding, use of safer, yet effective, oral anticoagulants, such as edoxaban, may be preferred over VKA.
Dr. Lanz reports employment at Daiichi Sankyo. Dr. Park reports institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche, The Medicines Company, Zora Biosciences. Dr. Antman reports receiving grant support through his institution from Daiichi Sankyo. Dr. Braunwald reports a research grant to his institution from Daiichi-Sankyo. Outside the submitted work, Dr. Braunwald reports research grants to his institution from AstraZeneca, GlaxoSmithKline, Merck, and Novartis; uncompensated consultancy and lectures from Merck and Novartis; consultancy with The Medicines Company and Theravance; payment for lectures from Medscape; and subcontract to his institution for his role as Network Chair for the NHLBI Heart Failure Network from Duke University. Dr. Giugliano reports clinical trials/research support: Amgen and Daiichi Sankyo. Honoraria for CME Lectures: Amgen, Daiichi Sankyo, Merck, and Servier. Consultant: Akcea, Amarin, American College of Cardiology, Amgen, Angel Med, Beckman-Coulter, Boehringer-Ingelheim, Bristol-Myers-Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lexicon, Merck, Portola, Pfizer, Servier, St Jude, Stealth Peptides. Acknowledgements
Role of the funding source Daiichi Sankyo Pharma Development funded the trial. The TIMI Study Group had full access to all data and performed the analyses. The first author wrote the initial draft and all authors participated in data interpretation and manuscript revisions, and had final responsibility for the decision to submit for publication.
The work described in the manuscript represents original work that has not been previously published and is not under consideration for publication elsewhere. Each of the authors has directly participated in the planning, execution and the analysis of this study, and qualify for authorship based on the ICMJE criteria. All authors have read and approved the final version submitted.
CRediT authorship contribution statement
Appendix A. Supplementary data
Anna Plitt:Investigation, Writing - original draft, Writing - review & editing.Christian T. Ruff:Conceptualization, Investigation, Writing review & editing.Assen Goudev:Conceptualization, Investigation, Writing - review & editing.Joao Morais:Conceptualization, Investigation, Writing - review & editing.Miodrag C. Ostojic:Conceptualization, Investigation, Writing - review & editing.Michael A. Grosso:Writing - review & editing.Hans J. Lanz:Writing - review & editing.Jeong-Gun Park:Formal analysis, Writing - review & editing.Elliott M. Antman:Conceptualization, Investigation, Writing - review & editing.Eugene Braunwald: Conceptualization, Investigation, Writing - review & editing.Robert P. Giugliano:Conceptualization, Methodology, Investigation, Writing original draft, Writing - review & editing, Visualization, Supervision, Project administration.
Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2020.01.009.
Declaration of competing interest Dr. Plitt reports receiving honoraria for educational activities from Bristol Myers Squibb. Dr. Ruff reports receiving research grants through institution: Boehringer Ingelheim, Daiichi Sankyo, MedImmune, National Institutes of Health. Honoraria for scientific advisory boards and consulting: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, MedImmune, Pfizer, Portola. Dr. Goudev reports receiving a research grant from Daiici Sankyo for Engage AT-TIMI 48 trial. Dr. Morais reports receiving honoraria from pharmaceutical companies for consulting activities and lectures: Amgen, Astra Zeneca, Bayer Healthcare, Boehringer Ingelheim, Novartis, Servier. Research grant from Daiichi Sankyo for Engage AT-TIMI 48 trial. Dr. Ostojic reports receiving a research grant from Daiichi Sankyo for Engage AT-TIMI 48 trial. Dr. Grosso reports employment at Daiichi Sankyo.
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Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AF-TIMI 48 trial Anna Plitt a, Christian T. Ruff b, Assen Goudev c, Joao Morais d, Miodrag C. Ostojic e, Michael A. Grosso f,1, Hans J. Lanz g, Jeong-Gun Park b, Elliott M. Antman b, Eugene Braunwald b, Robert P. Giugliano b,⁎ a
Mount Sinai Heart, New York, NY, United States of America TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, United States of America UMHAT “Tzaritza Yoanna-ISUL” EAD Clinic of Cardiology, Sofia, Bulgaria d Santo Andre's Hospital, Cardiology Division, Leiria, Portugal e School of Medicine University of Belgrade, Belgrade, Serbia f Daiichi Sankyo Inc., Basking Ridge, NJ, United States of America g Daiichi Sankyo Europe GmbH, Munich, Germany b c
a r t i c l e
i n f o
Article history: Received 25 October 2019 Received in revised form 30 November 2019 Accepted 8 January 2020 Available online xxxx Keywords: Atrial fibrillation Diabetes mellitus Non-vitamin K antagonist oral anticoagulants Stroke prevention
a b s t r a c t Background: Diabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/ benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest. Methods: 21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624). Results: On average, patients with diabetes were younger, and had a higher body mass index, CHA2DS2-VASc score and baseline endogenous Factor Xa activity. After multivariate adjustments, patients with diabetes had a similar rate of stroke and systemic embolism compared to those without diabetes (adjusted hazard ratio (HRadj) 1.08; 95% confidence interval (CI) 0.94–1.24; p = 0.28). However, the risk of major bleeding was significantly higher in patients with diabetes (HRadj 1.28; 95% CI 1.14–1.44; p b 0.001). The treatment effect of edoxaban (vs warfarin) was not modified by diabetes (all p-interactions N 0.05), a finding supported by the preserved edoxaban concentrations and inhibition of Factor Xa regardless of diabetes. The HRs of stroke and systemic embolism in patients receiving the higher-dose edoxaban regimen vs warfarin were 0.93 and 0.84 (pinteraction = 0.54) in those with and without diabetes respectively. The higher-dose edoxaban regimen reduced major bleeding (by 19–21%) and cardiovascular death (by 7–17%) regardless of diabetes (p-interactions = 0.81 and 0.33 respectively). Conclusion: Patients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes. © 2020 Elsevier B.V. All rights reserved.
1. Introduction Atrial fibrillation (AF) and diabetes mellitus are chronic conditions and both are independently associated with an increased risk of stroke and death [1,2]. AF is the most common chronic cardiac arrhythmia in the United States and worldwide [3] and is associated with a 4- to 5fold increased risk of stroke [4]. Diabetes is associated with a 2-fold excess risk of stroke [5], and longer duration of diabetes is linked with
⁎ Corresponding author at: TIMI Study Group, Hale BTM, Suite 7022, 60 Fenwood Road, Brigham and Women's Hospital, Boston, MA 02115, United States of America. E-mail address: [email protected] (R.P. Giugliano). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
even higher ischemic stroke rates [6]. These two conditions share similar risk factors including age, hypertension, and obesity [7], and are increasing in prevalence with the aging of the population [8,9]. Thus, further research among patients with both AF and diabetes, particularly as newer therapies are introduced, are of clinical interest. Edoxaban is a once-daily oral direct factor Xa inhibitor that is approved for the prevention of stroke and systemic embolic events (SEE) in patients with AF. In this manuscript from the pivotal phase 3 Effective aNticoaGulation with factor Xa next GEneration in Atrial Fibrillation– Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF–TIMI 48) trial [10], we compare adjusted outcomes in patients with vs without diabetes, report the pharmacokinetic and pharmacodynamic results, and the relative efficacy and safety of edoxaban compared to warfarin in patients stratified by diabetes status.
https://doi.org/10.1016/j.ijcard.2020.01.009 0167-5273/© 2020 Elsevier B.V. All rights reserved.
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
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2. Methods The design of the ENGAGE AF-TIMI 48 trial has been described previously [10,11]. In brief, this was a double-blind, double-dummy trial of 21,105 patients with AF at moderate-to-high risk of stroke randomized in 1:1:1 fashion to a higher-dose edoxaban regimen (HDER, 60 mg once daily), lower-dose edoxaban regimen (LDER, 30 mg once daily), or warfarin titrated to a target international normalized ratio (INR) of 2.0–3.0. A dose reduction of edoxaban by 50% in both edoxaban arms was mandated for any of the following: estimated creatinine clearance (CrCl) ≤ 50 mL/min using the Cockroft-Gault equation [12], weight ≤ 60 kg, or concomitant use of strong P-gp inhibitors. The primary efficacy endpoint was a composite of all stroke or SEE, and the principal safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Hemostasis (ISTH) [13]. Key secondary endpoints included cardiovascular death, stroke or SEE; major adverse cardiac events (MACE = MI, stroke, SEE, or death due to cardiovascular cause or bleeding); and the composite of all-cause death, stroke or SEE. Three net outcomes combing efficacy, safety, and mortality endpoints were analyzed: Primary = stroke, SEE, major bleeding, or death; Secondary = disabling stroke, life-threatening bleeding, or death; Tertiary = stroke, SEE, life-threatening bleeding, or death. The data were analyzed by pre-specified categories of diabetes (yes/ no) at randomization as determined by the local investigator. The subgroup of patients with diabetes was further stratified into non-insulin treated and insulin-treated diabetes. We hypothesized that the safety and efficacy of edoxaban would be preserved across subgroups stratified by diabetes status. Baseline characteristics were reported as percentages for categorical variables and were compared using the Chi-square test. Continuous variables were reported as medians with interquartile ranges and were compared using Wilcoxon rank-sum test or Kruskal-Wallis test of difference. Outcomes were presented as percentage of events per year and were compared using Cox proportional hazard models. Multivariate Cox regression models were used to adjust for baseline characteristics across the groups stratified by diabetes status. Covariates used for adjustment are shown in Table 1. The proportionality assumption was confirmed by assessment of Schoenfield residuals. There were no proportional hazards assumption violations for the study variables of history of diabetes and diabetes treatment status for the primary endpoints. Interactions between the randomized treatment and diabetes status were then tested by Cox proportional hazard modeling to address treatment-effect modification associated with diabetes. Differences between randomized treatment groups are presented as hazard ratios (HR) with 95% confidence intervals (CIs). HDER is the approved edoxaban regimen for stroke prevention in patients with AF, as the LDER was less effective than warfarin in preventing ischemic stroke. Therefore, we focused this analysis on the comparison of HDER vs warfarin and present data for the LDER in the Supplement. Endogenous FXa activity was measured at baseline and day 29 at peak and trough as previously described [14–16]. All analyses were performed using the SAS software, version 9.4 (SAS Institute Inc., Cary, NC). A 2-sided p b 0.05 was considered to indicate statistical significance, without adjustment for multiple comparisons. 3. Results Of the 21,105 patients who were enrolled in the ENGAGE AF-TIMI 48 trial, 7,624 (36%) had a history of diabetes (including 1,270 (6%) treated with insulin and 6,354 (30%) not receiving insulin) at randomization; 13,481 (64%) patients had no history of diabetes. Baseline characteristics differed by diabetes status (Table 1) but were similar by randomized treatment within each diabetes stratum (Supplementary Appendix Table S1). For example, patients with diabetes were on average
Table 1 Patient characteristics stratified by diabetes status. Characteristica Age (y), median (IQR) BMI (kg/m2), median (IQR) Weight (kg), median (IQR) Female Region North America Latin America Western Europe Eastern Europe Asia-Pacific and South Africa Prior stroke/TIA Congestive heart failure Hypertension Paroxysmal AF Prior VKA experienced Dose reduction at randomization CrCl (mL/min) ≤50 Weight ≤ 60 kg Use of verapamil/quinidine CHA2DS2VASc score Mean (SD) Median (IQR) N3 ≤3 CHA2DS2VASc score – without including diabetes in score Mean (SD) Median (IQR) N3 ≤3 Baseline laboratory studies Endogenous FXa activity (median, IQR) CrCl (mL/min), median (IQR) Platelet count (×103/μL) Hemoglobin (g/dL) NT-pro BNP (pg/mL) (median, IQR) hs-TNT (pg/mL) (median, IQR) GDF-15 (pg/mL) (median, IQR) Medication at time of randomization Aspirin Thienopyridine Amiodarone RAA inhibitor
Diabetes (N = 7,624)
No diabetes (N = 13,481)
70 (63, 76) 30.4 (26.9, 34.7) 87 (75, 102) 2782 (36.5)
73 (65, 78) 27.8 (24.8, 31.3) 79 (68, 91) 5258 (39.0)
2111 (27.7) 758 (9.9) 1242 (16.3) 2379 (31.2) 1134 (14.9) 1587 (20.8) 3681 (48.3) 7237 (94.9) 2014 (26.4) 4749 (62.3) 1491 (19.6) 1128 (14.8) 445 (5.8) 275 (3.6)
2570 (19.1) 1903 (14.1) 1994 (14.8) 4765 (35.3) 2249 (16.7) 4386 (32.5) 8443 (62.6) 12517 (92.8) 3352 (24.9) 7692 (57.1) 3865 (28.7) 2946 (21.9) 1638 (12.2) 486 (3.6)
4.6 (1.5) 5.0 (4.0–6.0) 5764 (75.6) 1860 (24.4)
4.2 (1.3) 4.0 (3.0–5.0) 9155 (67.9) 4326 (32.1)
3.6 (1.5) 4.0 (3.0–5.0) 3892 (51.0) 3732 (49.0)
4.2 (1.3) 4.0 (3.0–5.0) 9155 (67.9) 4326 (32.1)
N = 524 0.91 (0.80, 1.05) 76.6 (58.2–100.3) 196 (164–233) 13.9 (12.9–14.9) N = 3233 725 (350, 1306) N = 3214 14.6 (10.0, 21.9) N = 3214 1960 (1350, 2986)
N = 1037 0.88 (0.76, 1.01) 67.0 (52.0–86.9) 196 (164–231) 14.1 (13.1–15.1) N = 5509 865 (408, 1500) N= 5469 13.2 (9.4, 19.5) N = 5468 1529 (1111, 2162)
2400 (31.5) 205 (2.7) 797 (10.5) 5246 (68.8)
3780 (28.0) 282 (2.1) 1695 (12.6) 8660 (64.2)
AF, atrial fibrillation; CrCl, creatinine clearance; GDF-15, Growth Differentiation Factor-15; hs-TNT, high sensitivity cardiac troponin T; NT-proBNP, N-terminal pro b-type natriuretic peptide; RAA, rening, angiotensin, or aldosterone; TIA, transient ischemic attack; VKA, vitamin K antagonists. p b 0.001 for all comparisons except: p = 0.17 for Digoxin/Digitalis preperation use; p = 0.006 for thienopyridine use; p = 0.42 for platelet count. a Data shown are number (%) unless otherwise indicated. Data presented are median (interquartile ranges) for continuous variables and number (percentages) for categorical variables. Data for endogenous factor Xa activity are as a proportion of normal controls.
3 years younger (median 70 vs 73) and had a higher body mass index (BMIs) mean (31.3 vs 28.4 kg/m2) and CHA2DS2-VASc score (mean 4.6 vs 4.2) as compared to patients without diabetes (each p b 0.001). Excluding the 1 point for diabetes, the mean CHA2DS2-VASc score was 3.6 in patients with diabetes and 4.2 in those without diabetes (p b 0.001). This finding of an average of 0.6 more stroke risk factors other than diabetes in patients without diabetes likely was related to the minimum CHADS2 score of 2 that was required for participation in the trial (i.e., patients without diabetes had to have at least 2 of the other risk factors). The mean CHADS2 scores, excluding the point for diabetes, were 2.2 vs 2.7 (p b 0.001) for patients with and without diabetes. Among patients with diabetes, 20.8% had history of stroke/transient ischemic attack vs 32.5% of patients without diabetes (p b 0.001), and
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
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48.3% of patients with diabetes had history of congestive heart failure vs 62.6% without diabetes (p b 0.001). Patients with diabetes were less likely to meet edoxaban dose reduction criteria at randomization (19.6% vs 28.7%, p b 0.001), mostly driven by fewer patients having a creatinine clearance b 50 mL/min among patients with diabetes (14.8% vs 21.9%, p b 0.001). Among the 42% of patients participating in the biomarker substudy, patients with diabetes had higher median levels hs-TnT (14.6 vs 13.2 pg/mL) and GDF-15 (1960 vs 1529 pg/mL), but lower levels of NT-pro BNP (725 vs 865pg/mL) compared to patients without diabetes, p b 0.0001 for each of the 3 biomarkers (Table 1). Patients with diabetes had a higher median level of endogenous Factor Xa activity at baseline (0.91 vs 0.88, p = 0.0003) than those without diabetes. There were no statistically significant differences in the baseline characteristics between patients randomized to warfarin or edoxaban, either among patients with diabetes who were treated with or without insulin (Table S2).
3.1. Efficacy outcomes in patients by diabetes status The observed (unadjusted) rates of stroke/SEE in patients with and without diabetes were 1.61% vs 1.91%/year respectively, adjusted hazard ratio (HRadj was1.08, p = 0.28). After multivariate adjustment, the risk for several composite endpoints (including stroke, SEE, major bleeding, or death; disabling stroke, life-threatening bleeding, or death; and disabling stroke, SEE, life-threatening bleeding, or death) were significantly higher in patients with diabetes (Table 2). The adjusted risks of the primary and secondary efficacy endpoints were significantly higher among patients with diabetes treated with insulin compared to those without insulin-treated diabetes (Table S3). There was no difference in adjusted rates of stroke/SEE in patients with diabetes not receiving insulin vs patients without diabetes (HRadj 1.01; 95% CI 0.88–1.17; p = 0.85).
3.2. Safety outcomes in patients by diabetes status Major bleeding was significantly higher in patients with diabetes vs without diabetes (3.06%/year vs 2.57%/year, HRadj 1.28, p b 0.001) (Table 2). Similarly, the adjusted risks of major or CRNM bleeding (HR adj 1.10, p = 0.002) and all bleeding (HRadj 1.08, p = 0.008) also were significantly higher in patients with diabetes vs without diabetes. The higher rates of bleeding in patients with diabetes were driven by extracranial, non-fatal bleeding (2.59%/year vs 2.09%/year, HRadj 1.28, p b 0.001), since ICH (0.48%/year vs 0.49%/ year, HRadj 1.27, p = 0.09) and fatal bleeding (0.21%/year vs 0.25%/ year, HRadj 1.07, p = 0.73) were similar between the groups. Among patients with diabetes, the risk of major bleeding (Table S3) was highest in patients with diabetes treated with insulin (HR adj 1.31; 95% CI 1.05–1.61; p = 0.015).
3.3. Net outcomes in patients by diabetes status The annualized rate of the primary net outcome (composite of stroke, SEE, major bleed, or death) was increased in patients with diabetes as compared to patients without diabetes (7.65% vs 7.23%/year, HRadj 1.25, 95% CI 1.17–1.34, p b 0.001) (Table 2). A similar magnitude of increased adjusted risk in patients with diabetes was seen for the secondary (HRadj 1.26) and tertiary net outcomes (HRadj 1.27), both p b 0.001. Among patients with diabetes, the net outcomes were worst among patients treated with insulin (HRadj 1.57, 1.73 and 1.73 vs non-insulin treated diabetes for the 3 net outcomes, p b 0.0001 for each comparison, Table S3).
3
Table 2 Outcomes stratified by the presence of diabetes at randomization.
Efficacy endpoints Stroke/SEE Stroke Ischemic Hemorrhagic Nondisabling and nonfatal Disabling or fatal Fatal SEE Key secondary endpoints CV death, stroke or SEE MACE All-cause death, stroke or SEE All-cause mortality CV death Safety endpoints Major bleeding ICH Non-ICH Major or CRNM Fatal or life-threatening bleed Gastrointestinal bleeding All bleeding Net clinical outcomes Primary Secondary Tertiary
Diabetes (N = 7624) % patients/year
No diabetes (N = 13,481) % patients/year
Diabetes vs no diabetes HRadj (95%CI)
1.61 1.52 1.26 0.29 0.87
1.91 1.80 1.51 0.30 1.05
1.08 (0.94, 1.24) 1.07 (0.93, 1.23) 1.07 (0.92, 1.25) 1.11 (0.79, 1.54) 1.02 (0.85, 1.22)
0.70 0.39 0.10
0.77 0.43 0.13
1.19 (0.97, 1.48) 0.10 1.22 (0.92, 1.62) 0.16 1.09 (0.64, 1.87) 0.75
4.04 4.84 5.20
4.24 4.71 5.31
1.21 (1.11, 1.32) b0.001 1.28 (1.18, 1.38) b0.001 1.23 (1.14, 1.33) b0.001
4.09 2.87
4.02 2.87
1.30 (1.20, 1.42) b0.001 1.29 (1.17, 1.43) b0.001
3.06 0.48 2.59 11.6 0.73
2.57 0.49 2.09 10.5 0.72
1.28 (1.14, 1.44) 1.27 (0.96, 1.68) 1.28 (1.13, 1.46) 1.10 (1.04, 1.17) 1.20 (0.96, 1.50)
1.40
1.11
1.29 (1.08, 1.54) 0.004
14.8
13.4
1.08 (1.02, 1.14) 0.008
7.65 4.79 4.86
7.23 4.73 4.81
1.25 (117, 1.34) b0.001 1.26 (1.16, 1.37) b0.001 1.27 (1.17, 1.37) b0.001
p value
0.28 0.33 0.39 0.55 0.85
b0.001 0.09 b0.001 0.002 0.11
Adjusted hazard ratios and confidence intervals were derived from a Cox model adjusted for the following factors: age, body mass index (BMI), sex, Caucasian race, region, history of: stroke/transient ischemic attack (TIA), congestive heart failure, hypertension, paroxysmal atrial fibrillation, CrCl ≤ 50 mL/min at randomization, or use of: Vitamin K antagonist, strong P-gp inhibitor, aspirin, thienopyridine, amiodarone or digoxin/digitalis preparation at randomization. p values were calculated using the log rank test. CV, cardiovascular; CRNM, clinically relevant non-major; ICH, intracranial hemorrhage; MACE, MI, stroke, SEE, or death due to CV or bleeding; SEE, systemic embolic event. Primary net clinical endpoint is the composite of stroke, SEE, major bleeding, or death. Secondary net clinical endpoint is the composite of disabling stroke, life-threatening bleeding, or death. Tertiary endpoint is the composite of disabling stroke, SEE, life-threatening bleeding, or death.
3.4. Pharmacokinetics and pharmacodynamics 3.4.1. Edoxaban concentration and Factor Xa results at day 29 After stratification by the edoxaban dose received, the median trough concentrations of edoxaban, extrinsic anti-factor Xa activity at trough, and suppression of baseline endogenous factor Xa activity at peak and trough generally were similar in patients with diabetes as compared to those without diabetes (Table 3). In the HDER group that did not undergo dose reduction (i.e., patients who received 60 mg), there were significantly lower levels of edoxaban concentration (34.3 vs 37.2 ng/mL, p = 0.04) and suppression of endogenous factor Xa activity (−18% vs −24%, p = 0.0003) at trough in diabetics compared to non-diabetics, although these modest differences are of uncertain clinical significance.
3.4.2. International normalized ratio (INR) in the warfarin arm The median values for the time-in-therapeutic range (TTR) of the INR in the warfarin arm were similar among patients with diabetes vs without diabetes (68.6% vs 68.4%, p = 0.12), and in patients with diabetes who were treated with vs without insulin (68.2% vs 68.7%, p = 0.32)
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
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Table 3 Edoxaban concentration and anti-factor Xa results. Higher-dose edoxaban regimen Diabetes mellitus
No diabetes mellitus
Edoxaban patients who were not dose-reduced at randomization (HDER = 60 mg, LDER 996 Day 29 trough edoxaban concentration (ng/mL) N 34.3 Median (18.5, 60.8) IQR 439 Day 29 trough Anti-FXa activity (IU/mL) N 0.59 Median (0.33, 1.13) IQR 449 Day 29 peak endogenous FXa, % change from baseline N −67 Median IQR (−76, −52) 458 Day 29 trough endogenous FXa, % change from baseline N −18 Median (−30, −7) IQR
= 30 mg) 1507 37.2 (20.3, 62.8) 690 0.68 (0.39, 1.13) 738 −67 (−75, −52) 758 −24 (−34, −11)
Edoxaban patients who were dose-reduced at randomization (HDER = 30 mg, LDER = 15 mg) 562 259 Day 29 trough edoxaban concentration (ng/mL) N 26.3 28.7 Median (15.1, 43.1) (13.4, 48.4) IQR 223 91 Day 29 trough Anti-FXa activity (IU/mL) N 0.5 0.60 Median (0.3, 0.8) (0.30, 0.99) IQR 235 89 Day 29 peak endogenous FXa, % change from baseline N −58 −60 Median (−66, −44) (−67, −47) IQR 243 98 Day 29 trough endogenous FXa, % change from baseline N −18 −18 Median (−26, −7) (−28, −7) IQR
Lower-dose edoxaban regimen p value
0.04
0.11
0.66
0.0003
0.56
0.11
0.22
0.54
Diabetes mellitus
No diabetes mellitus
1021 17.7 (9.55, 31.6) 440 0.33 (0.20, 0.57) 478 −52 (−60, −35) 493 −11 (−20, −3)
1591 18.8 (10.3, 32.8) 662 0.36 (0.22, 0.58) 694 −50 (−60, −36) 723 −12 (−21, −5)
221 12.4 (7.13, 19.1) 75 0.27 (0.18, 0.47) 81 −36 (−47, −19) 86 −9 (−14, −3)
623 12.4 (7.51, 21.5) 235 0.27 (0.18, 0.43) 241 −39 (−45, −27) 251 −10 (−17, −3)
p value
0.14
0.21
0.43
0.09
0.24
0.57
0.56
0.46
Anti-FXa, anti-factor Xa; Diabetes Mellitus, diabetes mellitus; HDER, high dose edoxaban regimen; IQR, interquartile range; IU/mL, international units/mL; LDER, low dose edoxaban regimen; ng/mL, nanograms/mL.
(Table S4). Likewise, no differences were seen in the percentages of time with an INR b 2.0 or an INR N 3.0 in patients stratified by diabetes or among patients with diabetes treated with vs without insulin (Table S4). 3.5. Outcomes with high dose edoxaban vs warfarin 3.5.1. Efficacy endpoints There was no significant effect modification by diabetes status on the relative treatment effect of HDER as compared to warfarin for the primary endpoint of stroke or SEE (Fig. 1). Which is further illustrated by the Kaplan Meyer curves in Fig. S1 Panels A–B. Annualized rates of stroke or SEE in patients with diabetes randomized to HDER vs warfarin were 1.42% vs 1.52%/year (HR 0.93, 95% CI 0.71–1.23) and in patients without diabetes were 1.65% vs 1.96%/year (HR 0.84, 95% CI 0.70–1.02, p-interaction 0.54). Similarly, the reductions in composite and mortality endpoints with edoxaban were not modified by diabetes status (Fig. 1), even after further stratification by the presence or absence of dose reduction criteria (Tables S5A, S5B). 3.5.2. Safety and net outcomes HDER consistently reduced major bleeding compared to warfarin in patients with (3.20% vs 4.07%/year, HR 0.79, 95% CI 0.65–0.96) and without diabetes (2.68% vs 3.30%/year, HR 0.81, 95% CI 0.69–0.96, pinteraction 0.81; Fig. 1). Reductions in other bleeding endpoints and improved net outcomes with HDER compared to warfarin were similar in patients with vs without diabetes (Fig. 1). There were no significant effect modifications on safety endpoints or net outcomes with HDER vs warfarin when stratified by diabetes status in patients who were and were not dose reduced (Tables S5A and S5B). An analysis of the location of major bleeding events by treatment group showed similar patterns in patients with vs without diabetes, with lower rates in the edoxaban group in most locations, except for the gastrointestinal system which was increased with HDER (Tables S5A and S5B), but not with LDER, compared to warfarin.
3.6. Results by randomized treatment in patients with diabetes stratified by insulin use When the outcomes comparing HDER vs warfarin in patients with diabetes were analyzed and stratified by use of insulin, none of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification (Table S6), regardless of whether patients did not or did meet dose reduction criteria (Tables S7A and S7B). 3.7. Lower-dose edoxaban regimen There were no significant effect modifications by diabetes status on the relative treatment effect of LDER vs warfarin for efficacy, safety, or net outcomes (Fig. S2). 4. Discussion In this analysis of patients with AF stratified by diabetes status from a large randomized controlled trial of patients at moderate to high risk of stroke, we found that: 1) After adjustment for baseline characteristics, there was no significant difference in rates of stroke/SEE between patients with vs without diabetes, 2) Patients with diabetes had significantly higher adjusted risks of bleeding and death, particularly those treated with insulin, 3) The efficacy and safety profiles of edoxaban compared to warfarin were similar regardless of diabetes status. The similar pharmacokinetic (edoxaban concentrations) and pharmacodynamic (anti-factor Xa measures with edoxaban, INR with warfarin) results stratified by diabetes status help to explain the similar efficacy and safety profile of edoxaban relative to warfarin regardless of the presence or absence of diabetes. 4.1. Comparison with other studies of NOACs in AF Given the differences in the patient populations, dosing regimens, definitions of endpoints (particularly bleeding events), and methods
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
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<-- Better in Edoxaban Group
5
Worse in Edoxaban Group-->
Fig. 1. Key Outcomes by Treatment and Diabetes status. The rates of stroke and systemic embolic events, major bleeding and selected composite outcomes are shown, comparing the higher dose edoxaban regimen (HDER) with warfarin. CV, cardiovascular; MACE, MI, stroke, SEE, or death due to CV or bleeding; Primary net clinical outcome is composite of stroke, SEE, major bleeding, or death; SEE, systemic embolic event. 1p-interaction, interaction effect between history of diabetes and study treatment group (warfarin & high-dose edoxaban). Hazard ratios for higher-dose edoxaban regimen vs warfarin are shown in blue for patient with diabetes and in red for patients without diabetes. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
of analyzing patients with diabetes, it is challenging to compare results across the trials and registries of NOACs in patients with AF in the absence of direct comparisons. In the RE-LY trial, statistically significantly higher adjusted rates of stroke or SEE and major bleeding were reported in patients with diabetes compared to patients without diabetes [17]. In the ROCKET-AF trial, the observed (unadjusted) rates of stroke/SEE and major bleeding were similar in patients with vs without diabetes [18]. Post marketing data suggested increased rates of major bleeding in a diabetes cohort of 44,793 patients with AF treated with rivaroxaban as compared to those without diabetes [19]. In the ARISTOTLE trial, the adjusted rates of stroke/SEE were also similar in patients with and without diabetes, while bleeding rates were higher in patients with diabetes [20]. Furthermore, an adjusted analysis from the PREFER in AF (European Prevention of thromboembolic events-European Registry in Atrial Fibrillation) registry showed that among 1288 patients with diabetes, the 288 patients treated with insulin were at the highest risk of thromboembolism [21]. In a recent meta-analysis, the use of NOACs vs warfarin was noted to be associated with lower risk of stroke/SEE in patients with diabetes (Risk Ratio [RR] 0.80, 95% CI 0.68–0.93; p = 0.004) as well as lower risk of vascular death (4.97% vs 5.99%; RR 0.83, 95% CI 0.72–0.96; p = 0.01) [22]. Similar to our findings with edoxaban, there were no significant effect modifications due to diabetes on the efficacy and safety profiles of either dabigatran or rivaroxaban relative to warfarin in the RE-LY [17] or ROCKET-AF [18] trials, respectively. In the ARISTOTLE trial [20], the efficacy of apixaban was maintained in both the presence and absence of diabetes. However, while the rate of ISTH major bleeding in patients without diabetes was significantly reduced with apixaban relative to
warfarin (HR 0.60, 95% CI [0.51–0.72]), major bleeding rates with apixaban vs warfarin were similar in patients with diabetes (HR 0.96, 95% CI [0.74–1.25], p-interaction 0.003). A similar significant treatment interaction with diabetes was seen for the endpoint of major or clinically-relevant nonmajor bleeding (p b 0.001). Of note, patients with diabetes in ARISTOTLE had significantly higher rates of gastrointestinal (HR 1.50 95% CI (1.16–1.95)) and intraocular bleeding (HR 1.90 95% CI (1.06–3.42)) than patients without diabetes in ARISTOTLE. Further evaluation of bleeding with apixaban in patients with diabetes is needed to establish whether these observations in ARISTOTLE were due to the play of chance or represent a reduction in the safety margin of apixaban relative to warfarin in patients with diabetes. Thus edoxaban is the only NOAC shown to significantly reduce major bleeding in patients with diabetes mellitus. 4.2. Limitations These observations are derived from a clinical trial that enrolled patients with CHADS2 risk score of 2 or greater, all of whom were treated with an oral anticoagulant, and thus may not apply to the general population of patients with AF and diabetes seen in clinical practice. The trial entry criteria required a minimum CHADS2 score of 2, thus patients with diabetes tended to have relatively fewer of the other stroke risk factors as compared to patients without diabetes, since the presence of diabetes counted for 1 point towards the 2-point minimum. This may have partially mitigated the risk associated with diabetes in our dataset compared to that reported in unselected observational studies and trials with no minimum risk score. We acknowledge that despite
Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009
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the large sample size of the trial, the study was not powered for subgroup analyses. The presence of diabetes and treatments were determined at randomization and may have changed during the trial. We did not collect data on the duration or type of diabetes mellitus, nor were therapies for diabetes or their duration systematically reported after randomization. We also did not collect the quality of diabetes control during the trial. 5. Conclusion In the ENGAGE AF-TIMI 48 trial of patients with AF treated with oral anticoagulation, the adjusted rates of bleeding and mortality are higher in patients with diabetes as compared to those without diabetes. The efficacy (protection from stroke/SEE, reduction in cardiovascular mortality) and safety (reduction in bleeding, particularly ICH) profiles of edoxaban relative to warfarin were not modified by the presence of diabetes. Edoxaban concentration and anti-factor Xa effects were similar in patients with vs without diabetes. These consistent clinical and laboratory results make the higher dose edoxaban regimen an attractive alternative to warfarin in patients with or without diabetes. Since patients with insulin treated diabetes and AF are at higher risk for both stroke and bleeding, use of safer, yet effective, oral anticoagulants, such as edoxaban, may be preferred over VKA.
Dr. Lanz reports employment at Daiichi Sankyo. Dr. Park reports institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche, The Medicines Company, Zora Biosciences. Dr. Antman reports receiving grant support through his institution from Daiichi Sankyo. Dr. Braunwald reports a research grant to his institution from Daiichi-Sankyo. Outside the submitted work, Dr. Braunwald reports research grants to his institution from AstraZeneca, GlaxoSmithKline, Merck, and Novartis; uncompensated consultancy and lectures from Merck and Novartis; consultancy with The Medicines Company and Theravance; payment for lectures from Medscape; and subcontract to his institution for his role as Network Chair for the NHLBI Heart Failure Network from Duke University. Dr. Giugliano reports clinical trials/research support: Amgen and Daiichi Sankyo. Honoraria for CME Lectures: Amgen, Daiichi Sankyo, Merck, and Servier. Consultant: Akcea, Amarin, American College of Cardiology, Amgen, Angel Med, Beckman-Coulter, Boehringer-Ingelheim, Bristol-Myers-Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lexicon, Merck, Portola, Pfizer, Servier, St Jude, Stealth Peptides. Acknowledgements
Role of the funding source Daiichi Sankyo Pharma Development funded the trial. The TIMI Study Group had full access to all data and performed the analyses. The first author wrote the initial draft and all authors participated in data interpretation and manuscript revisions, and had final responsibility for the decision to submit for publication.
The work described in the manuscript represents original work that has not been previously published and is not under consideration for publication elsewhere. Each of the authors has directly participated in the planning, execution and the analysis of this study, and qualify for authorship based on the ICMJE criteria. All authors have read and approved the final version submitted.
CRediT authorship contribution statement
Appendix A. Supplementary data
Anna Plitt:Investigation, Writing - original draft, Writing - review & editing.Christian T. Ruff:Conceptualization, Investigation, Writing review & editing.Assen Goudev:Conceptualization, Investigation, Writing - review & editing.Joao Morais:Conceptualization, Investigation, Writing - review & editing.Miodrag C. Ostojic:Conceptualization, Investigation, Writing - review & editing.Michael A. Grosso:Writing - review & editing.Hans J. Lanz:Writing - review & editing.Jeong-Gun Park:Formal analysis, Writing - review & editing.Elliott M. Antman:Conceptualization, Investigation, Writing - review & editing.Eugene Braunwald: Conceptualization, Investigation, Writing - review & editing.Robert P. Giugliano:Conceptualization, Methodology, Investigation, Writing original draft, Writing - review & editing, Visualization, Supervision, Project administration.
Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2020.01.009.
Declaration of competing interest Dr. Plitt reports receiving honoraria for educational activities from Bristol Myers Squibb. Dr. Ruff reports receiving research grants through institution: Boehringer Ingelheim, Daiichi Sankyo, MedImmune, National Institutes of Health. Honoraria for scientific advisory boards and consulting: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, MedImmune, Pfizer, Portola. Dr. Goudev reports receiving a research grant from Daiici Sankyo for Engage AT-TIMI 48 trial. Dr. Morais reports receiving honoraria from pharmaceutical companies for consulting activities and lectures: Amgen, Astra Zeneca, Bayer Healthcare, Boehringer Ingelheim, Novartis, Servier. Research grant from Daiichi Sankyo for Engage AT-TIMI 48 trial. Dr. Ostojic reports receiving a research grant from Daiichi Sankyo for Engage AT-TIMI 48 trial. Dr. Grosso reports employment at Daiichi Sankyo.
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Please cite this article as: A. Plitt, C.T. Ruff, A. Goudev, et al., Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AFTIMI 48 trial, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.01.009