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)
Abstract
Background and Purpose—
Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA.
Methods—
ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0–3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin.
Results—
Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8–85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36–0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28).
Conclusions—
Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
Introduction
The risk of stroke in patients with atrial fibrillation (AF) is high,1 and it increases in the presence of other risk factors such as advanced age, congestive heart failure, hypertension, diabetes mellitus, and especially previous ischemic stroke (IS) or transient ischemic attack (TIA).2 However, even validated risk-stratification scores using these and additional risk factors, such as CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke) and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75: 2, diabetes, stroke: 2, vascular disease, sex female) scores2,3 may underestimate the true risk of stroke recurrence in patients with a previous IS or TIA,4,5 which might reach as high as 7% to 10% per year.4,6 Therefore, secondary prevention of stroke in these higher risk patients with AF is a major focus of cerebrovascular care.
For decades, vitamin K antagonists have been used for stroke prevention in patients with AF and previous stroke/TIA. Vitamin K antagonists are effective in reducing the risk of IS when compared with placebo7; however, they require regular monitoring of anticoagulation level and are subject to multiple drug–drug and food–drug interactions. More importantly, the risk of serious bleeding events, including intracranial hemorrhage (ICH) and fatal systemic bleeding in patients with AF, is increased.7–9
Non–vitamin K oral anticoagulants (NOACs) have been available since 2009 and have been demonstrated to be at least as effective as warfarin in preventing stroke or systemic embolic events (SEE) in patients with AF, whereas significantly reducing ICH.10–13 A recent meta-analysis of the 4 major phase III trials14 demonstrated relative reductions in ICH by 51% and mortality by 10% with NOACs compared with warfarin.
Among the NOACs, the directly acting, once-daily oral factor Xa inhibitor edoxaban, when compared with well-controlled warfarin, has been shown to be noninferior in preventing stroke or SEE and superior with lower rates of bleeding, ICH, cardiovascular mortality, and prespecified net clinical outcomes in the ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial.11 Furthermore, edoxaban markedly reduced hemorrhagic stroke, particularly in the first 6 months after randomization when compared with warfarin.15 In the present analysis, we sought to compare efficacy and safety of once-daily edoxaban with warfarin in patients with AF and a history of previous IS and TIA.
Methods
Study Population and Protocol
ENGAGE AF-TIMI 48 was a randomized, double-blinded, double-dummy trial that compared 2-dose regimens of once-daily edoxaban (higher-dose edoxaban regimen [HDER] 60 mg and lower-dose edoxaban regimen 30 mg) with warfarin (international normalized ratio, 2.0–3.0; median time-in-therapeutic range, 68.4%) in 21 105 patients with AF over a median of 2.8 years. The dose of edoxaban was reduced by 50% for patients with creatinine clearance of <50 mL/min, body weight of ≤60 kg, or concomitant use of a strong P-gp inhibitor. The design and results of ENGAGE AF-TIMI 48 have been published previously.11 Eligibility criteria included an age of ≥21 years, AF documented by electric tracing within the 12 months preceding randomization, a CHADS2 score of ≥2, and planned anticoagulation therapy for the duration of the trial. Patients with previous ICH, severe impairment of renal function (creatinine clearance <30 mL/min), increased bleeding risk, an alternate indication for anticoagulation, or requiring dual-antiplatelet therapy were excluded. As only the HDER is approved for the use by regulatory authorities worldwide, we focused on the comparison between HDER and warfarin in this article. We include results of the 7034 patients who were randomized to lower-dose edoxaban regimen in the online-only Data Supplement.
End Points
Primary end points in the ENGAGE AF-TIMI 48 trial were the composite of stroke (of any type) or SEE (efficacy) and major bleeding (safety). Detailed definitions of cerebrovascular end points have been published.11,15 IS was defined as an abrupt onset of focal neurological deficit caused by infarction with symptoms lasting for >24 hours or resulting in death in <24 hours. Nonfatal events lasting for <24 hours with complete neurological recovery were classified as TIAs. Primary hemorrhagic stroke included nontraumatic intraparenchymal, intraventricular, and subarachnoid hemorrhages. IS with hemorrhagic conversion was classified as a primary IS. ICH included subdural and epidural bleeds, as well as hemorrhagic stroke. All cerebrovascular events were adjudicated by independent stroke neurologists without the knowledge on the treatment assignment. Cardiovascular events, including acute coronary syndromes, SEE, death, and bleeding, were adjudicated by independent cardiologists without knowledge of treatment assignment.
Statistical Analysis
All efficacy analyses were performed in the intention-to-treat population and included all events after randomization. Bleeding events were analyzed in the safety population (all patients who took at least 1 dose of study drug) counting all hemorrhages that occurred through 30 days after the last dose. Hazard ratios (HRs) with 95% confidence intervals (CIs) comparing the relative efficacy and safety of edoxaban versus warfarin for the subgroup were calculated with the Cox proportional hazards models with treatment as a covariate along with the stratification factors of CHADS2 score and dose-adjustment status. Models were also constructed that evaluated the interaction between randomized treatment group and subgroups stratified by a history of IS/TIA before randomization. HRs with 95% CIs comparing patients with versus without a previous history of stroke/TIA were calculated using an adjusted Cox proportional hazards model, which included sex, age, race, geographic region, body mass index, smoking status, alcohol use, AF pattern, hypertension, coronary artery disease, dyslipidemia, congestive heart failure, diabetes mellitus, increased risk of falling, hepatic disease, neuropsychiatric disease, previous non-ICH bleed, the use of antiplatelet or nonsteroid anti-inflammatory drugs at randomization, and creatinine clearance at randomization. We also reported absolute risk differences of event rates per 10 000 patient-years between the edoxaban and the warfarin arms (calculated as the annualized event rate in the warfarin group minus the rate in the edoxaban group ×10 000). Analyses were performed independently by the TIMI Study Group using Stata v12.1 and SAS v9.2.
Results
There were 5973 (28.3%) patients with a history of IS and TIA enrolled in ENGAGE AF-TIMI 48 trial, of whom 67% had CHADS2 4 to 6 (compared with 5.1% in those without previous IS/TIA) and 36% were aged ≥75 years (Table 1). A history of previous IS/TIA was highest among patients enrolled from the Asia-Pacific/South Africa region (39.2%) and lowest among patients enrolled from the North America region (23.6%). A greater prevalence of congestive heart failure, diabetes mellitus, and elevated body mass index was present among patients without a history of IS/TIA (P<0.001). This observation may be explained by the protocol requirement for a minimum CHADS2 of 2 for trial participation; hence, patients without previous IS/TIA were enriched for other stroke risk factors. More patients with previous stroke/TIA had used vitamin K antagonist for at least 60 consecutive days before randomization (60.3% versus 58.4%, P=0.010).
| Characteristic | Previous Ischemic Stroke/TIA (n=5973; 28.3%) | No Previous Ischemic Stroke/TIA (n=15 132; 71.7%) | P Value |
|---|---|---|---|
| Age, y | |||
| Mean (SD) | 70.4 (9.2) | 70.7 (9.5) | <0.001 |
| Median (IQR) | 71 (64–77) | 72 (64–78) | |
| Male sex, n (%) | 3694 (61.8) | 9371 (61.9) | 0.91 |
| Region, n (%) | <0.001 | ||
| North America | 1105 (18.5) | 3576 (23.6) | |
| Latin America | 794 (13.3) | 1867 (12.3) | |
| Western Europe | 884 (14.8) | 2352 (15.5) | |
| Eastern Europe | 1863 (31.2) | 5281 (34.9) | |
| Asia-Pacific and South Africa | 1327 (22.2) | 2056 (13.6) | |
| Atrial fibrillation type, n (%) | n=5972 | n=15 127 | <0.001 |
| Paroxysmal AF | 1558 (26.1) | 3808 (25.2) | |
| Persistent AF | 1217 (20.4) | 3651 (24.1) | |
| Permanent AF | 3197 (53.5) | 7668 (50.7) | |
| Qualifying risk factor, n (%) | |||
| Age ≥75 y | 2119 (35.5) | 6355 (42.0) | <0.001 |
| Congestive heart failure | 2530 (42.4) | 9594 (63.4) | <0.001 |
| Diabetes mellitus | 1587 (26.6) | 6037 (39.9) | <0.001 |
| History of hypertension, n (%) | 5151 (86.2) | 14 603 (96.5) | <0.001 |
| CHADS2 score 4–6, n (%) | 4000 (67.0) | 768 (5.1) | <0.001 |
| Dose reduction, n (%) | 1734 (29.0) | 3622 (23.9) | <0.001 |
| Renal impairment (CrCl ≤50 mL/min) | 1214 (20.3) | 2759 (18.2) | <0.001 |
| Low body weight (≤60 kg) | 826 (13.8) | 1277 (8.4) | <0.001 |
| Use of verapamil or quinidine | 209 (3.5) | 465 (3.1) | 0.11 |
| VKA naïve, n (%) | 2369 (39.7) | 6294 (41.6) | 0.010 |
| Medication at randomization, n (%) | |||
| Aspirin | 1685 (28.2) | 4495* (29.7) | 0.031 |
| Thienopyridine | 218 (3.6) | 269 (1.8) | <0.001 |
| Amiodarone | 609 (10.2) | 1883 (12.4) | <0.001 |
| Digoxin or digitalis preparation | 1706 (28.6) | 4621 (30.5) | 0.005 |
Denominators are 5973 (previous stroke/TIA) and 15 132 (no previous stroke/TIA) unless otherwise indicated. AF indicates atrial fibrillation; CHADS2, congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke; CrCl, creatinine clearance; TIA, transient ischemic attack; and VKA, vitamin K antagonist.
*
15 129 patients had data.
Efficacy Outcomes
Overall, there was a higher rate of stroke/SEE among patients with previous IS/TIA when compared with those without (2.83% versus 1.42% per year; adjusted HR, 1.97; 95% CI, 1.73–2.24; P<0.001; Table I in the online-only Data Supplement). This difference was driven mainly by a higher annual rate of primary IS (2.35% versus 1.07%; adjusted HR, 2.19; 95% CI, 1.89–2.53) among patients with previous IS/TIA, whereas annual rates of primary hemorrhagic stroke were numerically, but not significantly higher (0.37% versus 0.27%; P=0.12). The adjusted risks for other stroke and efficacy outcomes were significantly increased among patients with previous IS/TIA (Table I in the online-only Data Supplement).
Analyses of the relative efficacy of HDER when compared with warfarin stratified by a previous history of stroke or TIA demonstrated no evidence of effect modification (Table 2). Among patients with previous IS/TIA, the HRs for HDER versus warfarin were 0.86 for stroke/SEE, 0.96 for primary IS, and 0.52 for primary hemorrhagic stroke (Figure 1). The 2-fold higher rate of stroke/SEE among patients with a previous IS/TIA translated into a numerically, but not significantly, larger absolute difference favoring edoxaban versus warfarin among patients with a previous IS/TIA (41 [−22 to 104] per 10 000 patient-years) compared with patients without a previous IS/TIA (17 [−11, 44]; Table 2).
| Warfarin (n=7036), n (%/y) | Higher-Dose Edoxaban (n=7035), n (%/y) | Higher-Dose Edoxaban vs Warfarin | ||||
|---|---|---|---|---|---|---|
| ARD per 10 000 Patient-Years (95% CI) | HR (95% CI) | P Value | PInter | |||
| Stroke/SEE | 0.86 | |||||
| Previous stroke/TIA | 145 (2.85) | 125 (2.44) | 41 (−22 to 104) | 0.86 (0.67–1.09) | 0.20 | |
| No previous stroke/TIA | 192 (1.41) | 171 (1.24) | 17 (−11 to 44) | 0.88 (0.72–1.08) | 0.22 | |
| CVD/stroke/SEE | 0.38 | |||||
| Previous stroke/TIA | 295 (5.77) | 242 (4.71) | 106 (18 to 195) | 0.82 (0.69–0.97) | 0.019 | |
| No previous stroke/TIA | 536 (3.93) | 486 (3.53) | 40 (−5 to 86) | 0.89 (0.79–1.01) | 0.08 | |
| All-cause death/stroke/SEE | 0.20 | |||||
| Previous stroke/TIA | 364 (7.12) | 303 (5.89) | 123 (24 to 222) | 0.83 (0.71–0.96) | 0.015 | |
| No previous stroke/TIA | 682 (5.00) | 646 (4.68) | 31 (−21 to 83) | 0.93 (0.84–1.04) | 0.22 | |
| MACE | 0.47 | |||||
| Previous stroke/TIA | 322 (6.36) | 273 (5.36) | 100 (6 to 194) | 0.84 (0.72–0.99) | 0.04 | |
| No previous stroke/TIA | 604 (4.46) | 554 (4.06) | 41 (−8 to 90) | 0.91 (0.81–1.02) | 0.10 | |
| All stroke | 0.84 | |||||
| Previous stroke/TIA | 136 (2.67) | 118 (2.30) | 37 (−24 to 98) | 0.86 (0.67–1.10) | 0.235 | |
| No previous stroke/TIA | 181 (1.33) | 163 (1.18) | 14 (−12 to 41) | 0.89 (0.72–1.10) | 0.280 | |
| Fatal stroke | 0.70 | |||||
| Previous stroke/TIA | 35 (0.67) | 30 (0.57) | 10 (−21 to 40) | 0.86 (0.53–1.40) | 0.54 | |
| No previous stroke/TIA | 51 (0.37) | 50 (0.36) | 1 (−13 to 15) | 0.97 (0.66–1.44) | 0.89 | |
| Nonfatal stroke | 0.94 | |||||
| Previous stroke/TIA | 107 (2.10) | 91 (1.77) | 33 (−21 to 87) | 0.84 (0.64–1.12) | 0.23 | |
| No previous stroke/TIA | 138 (1.01) | 116 (0.84) | 17 (−6 to 40) | 0.83 (0.65–1.06) | 0.14 | |
| Nondisabling, nonfatal stroke | 0.59 | |||||
| Previous stroke/TIA | 80 (1.56) | 69 (1.34) | 22 (−24 to 69) | 0.86 (0.62–1.18) | 0.35 | |
| No previous stroke/TIA | 110 (0.81) | 85 (0.62) | 19 (−1 to 39) | 0.76 (0.58–1.01) | 0.06 | |
| Disabling stroke | 0.22 | |||||
| Previous stroke/TIA | 30 (0.58) | 22 (0.42) | 15 (−12 to 43) | 0.73 (0.42–1.26) | 0.26 | |
| No previous stroke/TIA | 27 (0.20) | 32 (0.23) | −2 (−13 to 9) | 1.17 (0.70–1.96) | 0.54 | |
| Disabling or fatal stroke | 0.29 | |||||
| Previous stroke/TIA | 61 (1.17) | 51 (0.98) | 20 (−21 to 60) | 0.83 (0.58–1.21) | 0.34 | |
| No previous stroke/TIA | 74 (0.54) | 81 (0.58) | −5 (−22 to 13) | 1.09 (0.79–1.49) | 0.61 | |
| Primary hemorrhagic stroke | 0.85 | |||||
| Previous stroke/TIA | 31 (0.59) | 16 (0.31) | 29 (3 to 54) | 0.52 (0.28–0.94) | 0.03 | |
| No previous stroke/TIA | 59 (0.43) | 33 (0.24) | 19 (6 to 33) | 0.55 (0.36–0.85) | 0.007 | |
| Primary ischemic stroke | 0.70 | |||||
| Previous stroke/TIA | 109 (2.13) | 105 (2.04) | 9 (−47 to 65) | 0.96 (0.73–1.25) | 0.76 | |
| No previous stroke/TIA | 126 (0.92) | 131 (0.95) | −3 (−26 to 20) | 1.03 (0.81–1.32) | 0.81 | |
| All-cause death | 0.24 | |||||
| Previous stroke/TIA | 276 (5.19) | 231 (4.35) | 84 (1 to 167) | 0.84 (0.71–1.00) | 0.051 | |
| No previous stroke/TIA | 563 (4.03) | 542 (3.86) | 17 (−29 to 64) | 0.95 (0.85–1.07) | 0.43 | |
| CVD | 0.30 | |||||
| Previous stroke/TIA | 200 (3.76) | 157 (2.96) | 80 (10 to 150) | 0.79 (0.64–0.97) | 0.03 | |
| No previous stroke/TIA | 411 (2.94) | 373 (2.66) | 29 (−10 to 68) | 0.90 (0.78–1.04) | 0.14 | |
ARD indicates absolute risk difference, calculated as warfarin−edoxaban event rates, reported per 10 000 patient-years; CI, confidence interval; CVD, cardiovascular death; HR, hazard ratio; MACE, major adverse cardiac event; SEE, systemic embolic event; and TIA, transient ischemic attack.
As was observed in the overall population in the main trial, in the subgroup with previous IS/TIA, HDER significantly reduced cardiovascular death (HR, 0.79) and various composite end points that combined stroke and death, whereas there was a strong trend toward a reduction in all-cause mortality (HR, 0.84; P=0.051; Table 2). Patients without a history of IS/TIA experienced qualitatively similar benefits with HDER versus warfarin (Table 2). The absolute risk differences per 10 000 patient-years favoring edoxaban were numerically, but not significantly, greater among patients with versus without a previous IS for all 14 efficacy end points shown in Table 2.
Safety Outcomes
Annual rates of major hemorrhage (3.03% versus 2.64%; adjusted HR, 1.25; 95% CI, 1.10–1.41; P<0.001) and ICH (0.70% versus 0.40%; adjusted HR, 1.62; 95% CI, 1.22–2.14; P<0.001) were higher in patients with previous IS/TIA than in those without. Other safety outcomes were also significantly more frequent in patients with previous IS/TIA (Table II in the online-only Data Supplement), with the exception of fatal bleeding that had similar rates in patients with versus without previous IS/TIA.
There was no evidence of a significant treatment–subgroup interaction in the comparison of HDER versus warfarin for key safety outcomes when patients were stratified by a previous history of stroke/TIA (Table 3). As in the overall population, HDER significantly reduced the risk of ICH versus warfarin among patients with previous IS/TIA (0.62% versus 1.09%; absolute risk difference, 47 [8–85] per 10 000 patient-years; HR, 0.57 [0.36–0.92]; P=0.02; Figure 2), as well as significantly reducing life-threatening bleeding, major or clinically relevant nonmajor bleeding, and any bleeding (Table 3). Absolute risk differences between HDER and warfarin for most bleeding events were similar, regardless of the presence or the absence of previous IS/TIA, with the exception of fatal bleeding. There were 25 (2–47) versus 14 (0–27) fewer fatal bleeds per 10 000 patient-years with edoxaban among those with versus without a previous IS/TIA, respectively.
| Warfarin (n=7012), n (%/y) | Higher-Dose Edoxaban (n=7012), n (%/y) | Higher-Dose Edoxaban vs Warfarin | ||||
|---|---|---|---|---|---|---|
| ARD per 10 000 Patient-Years (95% CI) | HR (95% CI) | P Value | PInter | |||
| Major bleed | 0.60 | |||||
| Previous stroke/TIA | 167 (3.86) | 138 (3.25) | 61 (−19 to 141) | 0.84 (0.67–1.06) | 0.14 | |
| No previous stroke/TIA | 390 (3.47) | 306 (2.72) | 75 (29 to 121) | 0.79 (0.68–0.91) | 0.002 | |
| Major/clinically relevant nonmajor bleeding | 0.84 | |||||
| Previous stroke/TIA | 541 (14.29) | 460 (12.11) | 218 (54 to 381) | 0.85 (0.75–0.96) | 0.01 | |
| No previous stroke/TIA | 1269 (12.77) | 1115 (10.97) | 180 (84 to 275) | 0.86 (0.80–0.94) | <0.001 | |
| Fatal bleed | 0.39 | |||||
| Previous stroke/TIA | 18 (0.41) | 7 (0.16) | 25 (2 to 47) | 0.40 (0.17–0.95) | 0.04 | |
| No previous stroke/TIA | 41 (0.35) | 25 (0.22) | 14 (0 to 27) | 0.61 (0.37–1.01) | 0.055 | |
| Intracranial hemorrhage | 0.28 | |||||
| Previous stroke/TIA | 48 (1.09) | 27 (0.62) | 47 (8 to 85) | 0.57 (0.36–0.92) | 0.02 | |
| No previous stroke/TIA | 84 (0.73) | 34 (0.30) | 43 (25 to 62) | 0.41 (0.27–0.61) | <0.001 | |
| Any bleed | 0.47 | |||||
| Previous stroke/TIA | 643 (17.85) | 545 (14.88) | 297 (111 to 483) | 0.84 (0.75–0.94) | 0.002 | |
| No previous stroke/TIA | 1521 (16.08) | 1366 (14.09) | 199 (89 to 309) | 0.88 (0.82–0.95) | <0.001 | |
| Life-threatening bleed | 0.44 | |||||
| Previous stroke/TIA | 48 (1.09) | 29 (0.66) | 42 (3 to 82) | 0.61 (0.39–0.97) | 0.04 | |
| No previous stroke/TIA | 79 (0.68) | 38 (0.33) | 35 (17 to 54) | 0.48 (0.33–0.71) | <0.001 | |
| Net end points: death/stroke/systemic embolic event/major bleed | 0.32 | |||||
| Previous stroke/TIA | 479 (9.74) | 407 (8.24) | 150 (32 to 269) | 0.84 (0.74–0.96) | 0.01 | |
| No previous stroke/TIA | 983 (7.50) | 916 (6.89) | 61 (−4 to 126) | 0.92 (0.84–1.00) | 0.06 | |
| Death or disabling stroke | 0.12 | |||||
| Previous stroke/TIA | 298 (5.69) | 245 (4.67) | 100 (13 to 187) | 0.82 (0.69–0.97) | 0.02 | |
| No previous stroke/TIA | 580 (4.20) | 567 (4.08) | 12 (−36 to 60) | 0.97 (0.86–1.09) | 0.57 | |
| Death or disabling stroke or life-threatening bleed | 0.08 | |||||
| Previous stroke/TIA | 336 (6.50) | 266 (5.11) | 137 (44 to 230) | 0.79 (0.67–0.92) | 0.003 | |
| No previous stroke/TIA | 651 (4.75) | 617 (4.46) | 30 (−21 to 80) | 0.93 (0.84–1.04) | 0.23 | |
| Death or stroke or intracranial hemorrhage | 0.15 | |||||
| Previous stroke/TIA | 378 (7.42) | 306 (5.95) | 147 (47 to 247) | 0.80 (0.69–0.93) | 0.004 | |
| No previous stroke/TIA | 696 (5.11) | 648 (4.70) | 41 (−12 to 93) | 0.92 (0.82–1.02) | 0.11 | |
ARD indicates absolute risk difference, calculated as warfarin−edoxaban event rates, reported per 10 000 patient-years; CI, confidence interval; HR, hazard ratio; and TIA, transient ischemic attack.
In addition, as in the total trial population, among patients with previous IS/TIA, HDER reduced various net outcomes that included stroke, death, and bleeding (Table 3). This included a significant (P=0.003) reduction by 21% in a net outcome that included 3 of the most serious events—death, disabling stroke, or life-threatening bleeding. In patients without previous IS/TIA, the safety profile of HDER was qualitatively similar and also superior to warfarin (Table 3). In terms of absolute risk reductions, patients with a previous IS/TIA randomized to edoxaban had 4- to 8-fold larger absolute reductions in death or disabling stroke (100 [13–187] versus 12 [−36 to 60]) and the composite of death, disabling stroke, or life-threatening bleeding (137 [44–230] versus 30 [−21 to 80]) than was present in patients without a history of IS/TIA.
Lower-Dose Edoxaban Versus Warfarin
Data comparing the lower-dose edoxaban regimen with warfarin are shown in the Tables III and IV and Figures I and II in the online-only Data Supplement.
Discussion
We observed, in this prospectively planned subgroup analysis of the phase III randomized ENGAGE AF-TIMI 48 clinical trial, that patients with previous IS stroke/TIA were at high risk of recurrent stroke and bleeding related to anticoagulation, consistent with previous observations.4–9 Therefore, testing the effect of novel therapeutics, such as edoxaban, in this subgroup is relevant to clinical practice. As such, we found that patients with a previous IS/TIA experienced a similar relative, but greater absolute benefit, when compared with patients with no previous IS/TIA, when treated with the oral direct factor Xa inhibitor edoxaban instead of warfarin.
When compared with patients treated with warfarin, patients with previous IS/TIA randomized to HDER had significantly lower rates of primary hemorrhagic stroke (48% relative reduction), cardiovascular death (21%), major adverse cardiac events (16%), and various composite outcomes such as all-cause stroke/death/SEE (17%) and cardiovascular death/stroke/SEE (18%). These efficacy metrics are supported and, in part, might be explained by the favorable safety profile of the HDER in patients with previous IS/TIA demonstrating significant reduction in the rates of ICH (43% relative reduction), major and clinically significant nonmajor bleeding (15%), fatal (60%), life-threatening (39%), or any (16%) bleeding, as well as the net clinical end point outcomes such as death/stroke/SEE/major bleed (16%), death or disabling stroke (18%), death or disabling stroke or life-threatening bleed (21%), and death or stroke or ICH (20%). In addition, all-cause death was reduced by 16% (P=0.051) in patients with previous IS/TIA treated with HDER versus warfarin.
There are limited data on the NOAC use in patient populations at high risk for recurrent events, including those with previous IS/TIA. With exception of a recent analysis of rivaroxaban use in a number of higher-risk populations from the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial,16 our study is the first to provide the dedicated data in support of safety and efficacy of NOAC use in patients with previous IS/TIA.
Previous data11,14,15 indicate that the reduction of hemorrhagic event rates (particularly intracranial bleeding) represents this primary clinical benefit of edoxaban over warfarin. In this analysis, the rates of ischemic and hemorrhagic events were higher in the patients with previous IS/TIA than in those without a previous IS/TIA, despite having fewer traditional stroke risk factors. This observation is not entirely unexpected because patients with AF are thought to have a distinct pathophysiology of stroke related to thromboembolism, rather than the mechanisms of stroke related to atherosclerosis of cerebral vessels.17,18 Additional risk of stroke recurrence in patients with AF might come from insufficient anticoagulation, or ineffective control of other vascular pathologies. Regarding the increased risk of hemorrhagic events in patients with AF with previous IS/TIA, there are several factors that might be contributory. First, older individuals and those with supratherapeutic anticoagulation with warfarin have higher risks of intracerebral and subdural hemorrhage.19 Furthermore, a history of cerebrovascular disease is an independent predictor of intracerebral hematoma (odds ratio, 3.1; 95% CI, 1.7–5.6) among outpatients taking warfarin,19 underscoring the potential mechanisms by which previous stroke might increase the risk of intracerebral hemorrhage including (1) underlying small cerebral vessel disease such as cerebral amyloid angiopathy20 or (2) the presence of the subclinical (silent) or occult brain infarcts that may predispose to brain hemorrhage.21
When warfarin-related intracerebral hemorrhage occurs, stroke mortality rate doubles in a dose-dependent manner,22 likely related to the large size of hematoma.23 Thus, preventing hemorrhagic cerebrovascular events is of paramount importance for those patients who require anticoagulation because of high risk of recurrent embolic stroke. In this analysis, patients with previous IS/TIA randomized to HDER experienced similar protection from arterial thromboembolism and death when compared with well-managed warfarin (median time-in-therapeutic range 68.4%) and superior protection from primary hemorrhagic stroke and ICH, similar to the overall ENGAGE AF-TIMI 48 cohort.11
However, because patients with previous IS/TIA were at a substantially higher risk of recurrent stroke, ICH, and death compared with those without a history of stroke/TIA, the absolute risk reductions favoring edoxaban were numerically magnified by a factor of 2- to 8-fold for several cerebrovascular and mortality end points, including stroke/SEE, all-cause mortality, cardiovascular death, and a variety of composite end points in those with previous cerebrovascular events. These data highlight an additional advantage of edoxaban’s favorable safety profile in patients with previous IS/TIA, which along with the facilitation of patient compliance of once-daily dosing without need for routine monitoring, make edoxaban an attractive option for anticoagulation among patients with AF and a previous cerebrovascular ischemic event.
Conclusions
Patients with history of IS and TIA represent a vulnerable population of patients with AF, who are highly prone for recurrent cerebrovascular events. In this prespecified analysis of a large, randomized double-blind trial of patients with AF, we demonstrated that on account of higher ischemic and hemorrhagic event rates, patients with AF and a history of previous IS/TIA have generally greater absolute benefits from once-daily edoxaban versus well-managed warfarin, when compared with AF patients without a history of previous IS/TIA. Furthermore, the superior safety profile of edoxaban extends to these patients with previous stroke/TIA, all of whom have a strong indication for anticoagulation for secondary stroke prevention.
Supplemental Material
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© 2016 American Heart Association, Inc.
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History
Revision received: 22 May 2016
Received: 24 May 2016
Accepted: 24 May 2016
Published online: 7 July 2016
Published in print: August 2016
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Dr Rost, Dr Norden, Dr Silverman, and Dr Singhal report receiving honoraria from Daiichi Sankyo for work as members of the Clinical End point Committee for the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. Dr Giugliano reports receiving consulting fees from American College of Cardiology, Boehringer-Ingelheim, Daiichi Sankyo, Janssen Pharmaceuticals, Merck, Pfizer, and Portola; lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, Merck, and Sanofi; and grant support through his institution from Daiichi Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Dr Ruff reports grant support through his institution (Brigham and Women’s Hospital) from Daiichi Sankyo and has served as a consultant and received honoraria from Daiichi Sankyo, Boehringer Ingelheim, Bayer, and Portola. Ms Murphy, Ms Crompton, Dr SomaRaju, and Dr Antman report receiving grant support through their institution from Daiichi Sankyo for their roles in the ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial. Dr Nicolau reports research funding from Boehringer Ingelheim, Bayer, and Bristol-Myers Squibb and receiving grant support through his institution from Daiichi Sankyo for his role in the ENGAGE AF-TIMI 48 trial. He also reports honoraria from Bristol-Myers Squibb and a consultancy/advisory for Bayer. Dr Mercuri reports being an employee of Daiichi Sankyo and holding a pending patent related to the clinical properties of edoxaban. Dr. Braunwald reports receiving consulting fees from Sanofi, the Medicines Company, and Theravance; lecture fees from Daiichi Sankyo, Menarini, Medscape, and Bayer HealthCare; and grant support through his institution from Daiichi Sankyo, AstraZeneca, Johnson & Johnson, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Novartis, and Sanofi-Aventis. He also reports serving as an unpaid consultant for Merck.
Sources of Funding
This study was supported by Daiichi-Sankyo Pharma Development, Edison, NJ.
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