MD Conference Express AHA 2013 - (Page 27)
stenosis. Secondly, he pointed out that these results should
not be applied to other etiologies of RAS including arteritis
or firbromuscular dysplasia. He concluded by stating that
CORAL showed that renal artery stenting for moderate RAS
lesions does not improve clinical outcomes but that the
impact of treatment for patients with severe lesions could
not be definitively concluded through the CORAL results.
Edoxaban Noninferior to Warfarin in
the ENGAGE AF-TIMI 48 Trial
Written by Muriel Cunningham
Warfarin is widely used for stroke prevention in patients
with atrial fibrillation (AF) but novel oral anticoagulants
have been developed that may be just as effective
[Dogliotti A et al. Clin Cardiol 2013]. Edoxaban is a direct
oral factor Xa inhibitor administered once daily with a
rapid onset of action. Warfarin and two doses of edoxaban
were compared in the Anticoagulation With Factor Xa
Next Generation in Atrial Fibrillation - Thrombolysis in
Myocardial Infarction 48 study [ENGAGE AF-TIMI 48;
Giugliano RP et al. N Engl J Med 2013]. This trial enrolled
21,105 patients with AF at moderate to high risk of stroke
(CHADS2 ≥2) at 1393 centers in 46 countries. Patients were
randomized in a double-blind, double-dummy manner
to one of three regimens: 1) warfarin to an international
normalized ratio (INR) of 2.0 to 3.0 (n=7036); 2) edoxaban
60 mg/day (high dose; n=7035); or 3) edoxaban
30 mg/day (low dose; n=7034). Edoxaban doses were
decreased by 50% if patients had a creatinine clearance
of 30 to 50 mL/minute, had a body weight ≤60 kg, or were
taking a strong P-glycoprotein inhibitor. The primary
endpoint was a composite of stroke or systemic embolic
events (SEE). The primary analysis was a noninferiority
comparison performed in those patients who took at
least one dose of study medications (modified intentionto-treat [mITT] population) during the time that patients
were treated (on-treatment time period). Secondary
analyses evaluated all patients randomized during the
overall treatment period (ITT).
Robert P. Giugliano, MD, Brigham and Women's
Hospital, Boston, Massachusetts, USA, presented the
primary results from the ENGAGE AF-TIMI 48 trial.
Demographic characteristics were well-balanced with no
differences between treatment groups in any variable. The
median participant age was 72 years (interquartile range,
64 to 78 years), 38% were female, and the mean CHADS2
score was 2.8±1.0. In terms of medical history, 94% had
hypertension, 57% had prior congestive heart failure,
36% had diabetes mellitus, and 28% had a prior stroke or
transient ischemic attack. A quarter of the patients had an
edoxaban dose reduction at randomization.
Over 99% of the patients completed the trial, and only
one patient was lost to follow-up. Overall the median
time in the therapeutic range was 68.4% (interquartile
range, 56.5 to 77.4). The primary endpoint was based on
a median follow-up of 2.8 years. Both doses of edoxaban
met the noninferiority criteria (p<0.0001 for high-dose
edoxaban and p=0.005 for low-dose ; Figure 1) in the mITT
population while on treatment. Neither edoxaban regimen
was statistically superior for the primary endpoint (p=0.08
for high dose and p=0.10 for low dose in the ITT analysis
during the overall time period; Figure 1). Both doses of
edoxaban had significant reductions in key secondary
outcomes (Figure 2) and safety endpoints (Figure 3).
Figure 1. Primary Endpoint Results
15. Giugliano; Figure 1: Primary Endpoint Results
Noninferiority Analysis (mITT, On Treatment)
Hazard Ratio (97.5 % CI)
Warfarin TTR 68.4%
p Values
Noninferiority
Superiority
p<0.0001
p=0.017
p=0.005
p=0.44
0.79
Edoxaban 60 mg QD*
vs warfarin
1.07
Edoxaban 30 mg QD*
vs warfarin
0.50
1.0
1.38
2.0
Edoxaban Noninferior
Superiority Analysis (ITT, Overall)
Hazard Ratio (97.5 % CI)
0.87
Edoxaban 60 mg QD*
vs warfarin
p Value
for superiority
p=0.08
p=0.10
1.13
Edoxaban 30 mg QD*
vs warfarin
0.50
1.0
Edoxaban
Superior
Edoxaban
Inferior
2.0
Both dose regimens of edoxaban were noninferior to warfarin in the primary noninferiority
analysis. The high-dose regimen tended to be more effective at reducing stroke/SEE compared
with warfarin and the low-dose regimen less effective.
Reproduced with permission from RP Giugliano, MD.
Figure 2. Secondary Endpoint Results
Edoxaban 60 mg QD*
vs warfarin
p Value vs
Warfarin
Edoxaban 30 mg QD*
vs warfarin
Warfarin TTR 68.4% HR (95% CI)
E-60
0.54
0.33
Hem. Stroke
1.00
Ischemic Stroke
<0.001
1.41
0.97
<0.001
2º EP: Stroke, SEE, CV death
Death or ICH
0.87
0.95
0.005
0.32
0.87
0.82
All-Cause Mortality
CV Death
0.004
<0.001
0.92
0.87
0.86
0.85
Myocardial Infarction
0.25
E-30
<0.001
0.94
0.08
0.006
0.013
0.60
1.19
0.5
edoxaban superior
1.0
0.008
0.13
2.0
edoxaban inferior
Both dose regimens of edoxaban reduced hemorrhagic stroke, death or ICH, and CV death
compared with warfarin. The low-dose regimen was not as effective as warfarin at reducing
ischemic stroke. CV=cardiovascular; E-60=edoxaban 60 mg QD dose group; E-30=edoxaban 30
mg QD dose group; ICH=intracerebral hemorrhage; SEE=systemic embolic events, TTR=time
in therapeutic range.
Reproduced with permission from RP Giugliano, MD.
Official Peer-Reviewed Highlights From the American Heart Association Scientific Sessions 2013
27
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