standard medical therapy tra 40 mg + 2.5 mg/d tra 40 mg + 2.5 mg/d placebo ep:cv...
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Standard Medical TherapyStandard Medical Therapy
TRA40 mg + 2.5 mg/d
TRA40 mg + 2.5 mg/d
PlaceboPlacebo
1 EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc.EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc.2 EP: CV Death/MI/strokeEP: CV Death/MI/stroke1 EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc.EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc.2 EP: CV Death/MI/strokeEP: CV Death/MI/stroke
Double-blindDouble-blindDouble-blindDouble-blind
Patients with high-risk Non-ST-Segment Elevation Acute Patients with high-risk Non-ST-Segment Elevation Acute Coronary Syndrome Coronary Syndrome <<24h of symptoms24h of symptoms
Patients with high-risk Non-ST-Segment Elevation Acute Patients with high-risk Non-ST-Segment Elevation Acute Coronary Syndrome Coronary Syndrome <<24h of symptoms24h of symptoms
N=10,000N=10,000N=10,000N=10,000
Follow-Up Day 30; 4, 8, 12 Months; Every 6 months after 1st year
Follow-Up Day 30; 4, 8, 12 Months; Every 6 months after 1st year
Duration: >1 year follow-up; >2334 1 EP and >1457 key 2 EP events
Duration: >1 year follow-up; >2334 1 EP and >1457 key 2 EP events
1:11:1
TRA•CER Study DesignTRA•CER Study Design
TRA ProgramTRA Program
Primary EP: Composite of CV Death, MI, Stroke, Primary EP: Composite of CV Death, MI, Stroke, Recurrent Ischemia with Rehosp, Recurrent Ischemia with Rehosp,
Urgent Coronary RevascularizationUrgent Coronary Revascularization
Primary EP: Composite of CV Death, MI, Primary EP: Composite of CV Death, MI, Stroke and Urgent RevascularizationStroke and Urgent Revascularization
F/U: 30 Days, 4, 8, 12 months and 6 months thereafter1 yr minimum, event driven
SCH530348 SCH530348Placebo Placebo
TRA ProgramTRA Program29,500 patients29,500 patients
Age Distribution of People With AFAge Distribution of People With AFCompared With U.S. General PopulationCompared With U.S. General Population
Arch Int Med. 1995;155:471.
Age (years)
Population withAtrial Fibrillation
U.S. Population
U.S
. P
op
ula
tio
n (
x 10
00)
5–95–9<5 10–14
15–1920–24
25–2930–34
35–3940–44 50–54 60–64 70–74 80–84 90–94
45–49 55–59 65–69 75–79 85–89 >95
AF
Po
pu
lati
on
(x
10)
0
10.000
20,000
30,000
0
100
200
300
400
500
Warfarin for Atrial FibrillationWarfarin for Atrial FibrillationLimitations Lead to Under-treatmentLimitations Lead to Under-treatment
0
20
40
60
80
<55<55 55-6455-64 65-7465-74 75-8475-84 8585
44%44%
58%58%61%61%
57%57%
35%35%
Age (years)Age (years)
Wa
rfa
rin
Us
e in
Wa
rfa
rin
Us
e in
Elig
ible
Pat
ien
ts (
%)
Elig
ible
Pat
ien
ts (
%) 55% 55%
Overall Overall UseUse
Go A et al. Go A et al. Ann Intern MedAnn Intern Med 1999;131:927. 1999;131:927.
WarfarinWarfarinBattling All Comers for Over a DecadeBattling All Comers for Over a Decade
Warfarin vs placeboWarfarin vs placebo
Warfarin vs ASAWarfarin vs ASA
Warfarin vs ASA + fixed dose wafarinWarfarin vs ASA + fixed dose wafarin
Warfarin vs DTIWarfarin vs DTI
Warfarin vs dual antiplateletWarfarin vs dual antiplatelet
RELYDabigatran for stroke prevention in atrial fibrillation
Non-valvular atrial fibrillation at moderateto high risk of stroke or systemic embolism
(at least one high risk factor)
R
Warfarin1 mg, 3mg, 5 mg
(INR 2.0-3.0)N=6000
Dabigatran Etexilate 110 mg b.i.d.
N=6000
Dabigatran Etexilate 150 mg b.i.d.
N=6000
•Primary objective: Noninferiority to warfarin
•Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up.
•Primary end point: Stroke + systemic embolism
Atrial Fibrillation with At Least One Additional Risk Factor for Stroke
Apixaban placebo twice dailyApixaban placebo twice daily++
Warfarin (target INR 2-3)Warfarin (target INR 2-3)
Apixaban 5 mg oral twice dailyApixaban 5 mg oral twice daily++
Warfarin placeboWarfarin placebo
Primary outcome: stroke and systemic embolismPrimary outcome: stroke and systemic embolism
Other outcomes: Death, MI, bleedingOther outcomes: Death, MI, bleedingStratified by warfarin-naïve statusStratified by warfarin-naïve status
448 events over anticipated 2 year median follow-up; 448 events over anticipated 2 year median follow-up; >90% power to show non-inferiority >90% power to show non-inferiority
(apixaban vs warfarin upper bound of 95% CI <1.38)(apixaban vs warfarin upper bound of 95% CI <1.38)
RandomizeRandomizeDouble blindDouble blind(n = 15,000)(n = 15,000)
Age ≥ 75 years Prior stroke, TIA or SE CHF or LVEF ≤ 40% Diabetes mellitus Hypertension
Age ≥ 75 years Prior stroke, TIA or SE CHF or LVEF ≤ 40% Diabetes mellitus Hypertension
Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device
ARISTOTLE
ARISTOTLE
9
Rivaroxaban Warfarin
Primary Endpoint: Stroke or non-CNS Systemic Embolism
Statistics: non-inferiority, >95% power, 2.3% warfarin event rate
INR target - 2.5 (2.0-3.0 inclusive)
20 mg daily15 mg for Cr Cl 30-
49
Atrial Fibrillation
RandomizeDouble blind / Double Dummy
(n ~ 14,000)
Risk FactorsRisk Factors• CHF CHF • Hypertension Hypertension • Age Age 75 75 • Diabetes Diabetes OROR• Stroke, TIA or Systemic Stroke, TIA or Systemic
embolus embolus
At least 2 At least 2 requiredrequired
Monthly Monitoring and adherence to standard of care guidelines
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