Post on 06-May-2015
description
Edoxaban versus Warfarin in Patients
withAtrial Fibrillation
Robert P.Giugliano et alNew Engl JMed Nov 19,2013
Effective ANticoaGulation with
Factor XA next GEneration in
Atrial Fibrillation – Thrombolysis In
Myocardial Infarction 48 (ENGAGE AF TIMI 48)
Introduction
• Atrial Fibrillation (AF) is the most common type of arrhythmia.
• It is a supraventricular arrhythmia characterized
electrocardiographically by low amplitude baseline oscillations
(fibrillatory or f waves) and an irregularly irregular ventricular
rhythm.
• Thromboembolic complications are common with AF.
• Warfarin has been the sole effective agent in preventing
thromboembolic complications in pts with AF,but with risk of
hemorrhage.
• Newer agents came into usage and are in pipeline ,as efficacious
as warfarin but with decreased risk of hemorrhage.
Background
• Edoxaban is a oral, reversible,direct factor Xa inhibitor, having
linear and predictable pharmacokinetic profile.
• 62% bioavailability, with proven antithrombotic effects.
• Max. conc. within 1-2 hours and 50% is excreted by the kidney.
• The long term efficacy and safety of edoxaban as compared
with warfarin in patients with AF is not known.
Two dose regimens of once daily edoxaban with
warfarin in patients with AF who were at
moderate to high risk for stroke.
Trial design
• It is a three group, randomized, double blind, double
dummy trial comparing two dose regimens of edoxaban
with warfarin.
• 1393 centers in 46 countries.
• November 19, 2008 through November, 2010.
Inclusion criteria
Randomized and study drugs
• Patients were randomly assigned in a 1:1:1 ratio, to receive warfarin,
dose adjusted to achieve an INR of 2.0 to 3.0,or to receive high
dose(60mg) or low dose edoxaban(30mg).
• Randomization of patients who were already on vitamin K antagonist
was done after their INR was 2.5 or less.
• Randomization was stratified according to
CHADS2 score of 2 or 3 vs 4,5,6
Status with respect to the need for reduction in the edoxaban dose.
Dose of edoxaban was halved in case …
• At the time of randomization or during the study if…
Estimated CrCl <30 to 50 ml/min.
A body weight of <60kg
Concomitant use of P-glycoprotein inhibitors
(verapamil or quinidine,dronedarone).
P Glycoprotein inhibitors• Permeability glycoprotein, abbreviated as P-gp or Pgp • Also known as multidrug resistance protein 1 (MDR1) or ATP-
binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243)
• Encoded by the ABCB1 gene.• Expressed in the intestinal epithelium, hepatocytes, renal PCT cells,
adrenal gland and capillary endothelial cells comprising the BBB.
• It is inhibited by many drugs, such as: Amiodarone,Azithromycin Captopril,Clarithromycin,Cyclosporine Quinidine,Quinine, Reserpine,Ritonavir Verapamil
Study end points
The primary efficacy end point
• Time to the first adjudicated stroke (ischemic or hemorrhagic)
• Systemic embolic event (SEE).
The principal safety end point was
• Adjudicated major bleeding during treatment ,as defined by the
International Society on Thrombosis and Haemostasis.
Secondary composite end points
• Stroke,SEE,death from CV causes,MI.
Net clinical end points
• included the above all.
Results
• Total of 21,105 pts underwent randomization.
• 21,026(99.6%) received the study drug.
• A total of 5330(25.3%) received a reduced dose of edoxaban or
matching placebo at randomization.
• After randomization , dose reductions occurred in 7.1% pts,and dose
increases in 1.2% with similar rates in three treatment groups.
• Median duration of treatment exposure was 907 days, excluding
interruptions.
• Median follow up was 1022 days.
Primary end point
EVENTS WARFARIN GROUP
HIGH DOSE EDOXABAN
P VALUE LOW DOSE EDOXABAN
P VALUE
STROKE or SYSTEMIC EMBOLISM
232 (1.50%/yr) 182 (1.18%/yr) P<0.001P=0.02
253 (1.61%/yr)
P=0.005P=0.44
ANNUALIZED RATE (ITT)
1.80%/yr 1.57%/yr 2.04%/yr
HEMORRHAGIC STROKE
0.47% 0.26% P<0.001 0.16% <0.001
ISCHEMIC STROKE
1.25% 1.25% 1.77%
MAJOR BLEEDING EVENTS
3.43% 2.75% 1.61%
LIFE THREATENING BLEEDING
0.78% 0.40% 0.25%
Bleeding
OUTCOME WARFARIN(%of pts/yr)
HIGH DOSE EDOXABAN
LOW DOSE EDOXABAN
P VALUE
MAJOR BLEEDING 524 (3.43%) 418 (2.75%) 254 (1.61%) <0.001
FATAL 59 (0.38%) 32 (0.21%) 21 (0.13%) <0.001
IC BLEED 132 (0.85%) 61 (0.39%) 41(0.26%) <0.001
FATAL IC BLEED 42(0.27%) 24 (0.15%) 12 (0.08%) <0.001
GI BLEED 190 (1.23%) 232 (1.51%) 129 (0.82%) <0.001
LIFE THREATENING BLEED
122 (0.78%) 62 (0.40%) 40 (0.25%) <0.001
MINOR BLEEDING 714 (4.89%) 604 (4.12%) 533 (3.52%) <0.001
GI bleed more in high dose edoxaban
Secondary and other efficacy outcomes
• Rates of all three prespecified secondary composite
outcomes were significantly lower with high dose
edoxaban
• Lower annualized rates of CV death with edoxaban
(2.74% vs 3.17%).
HIGH DOSE EDOXABAN < WARFARIN
LOW DOSE EDOXABAN =WARFARIN
Discussion
• Both doses of edoxaban were non inferior to warfarin.• High dose edoxaban more effective than warfarin.• Rate of ischemic strokes high dose edoxaban = warfarin <
low dose edoxaban.• Rate of hemorrhagic strokes,CV deaths less in edoxaban
groups.• All bleedings except GI bleed were low in edoxaban
group.
Comparison of edoxaban regimensRate of stroke,systemic
embolic event
Reduction in incidence of ischemic strokes (29%)
Hemorrhagic strokes (49 vs 33
events)
No significant differences between the two edoxaban groups in the rates of death from cardiovascular causes and death from any cause
HIGH DOSE EDOXABAN vs LOWDOSE EDOXABAN
Anticoagulants
Warfarin50yrs
Rodent poison
Dabigatran
Factor IIa inhibitor
RivaroxabanFactor Xa inhibitor
ApixabanFactor
xa inhibitor
Edoxaban
Factor Xa
inhibitor
Warfarin• Water soluble VKA,initially developed as rodenticide.• Inhibits synthesis of vitamin K dependent clotting factors –
II,VII,IX,X and anticoagulants proteins C and S.• Inhibits VKOR,thereby blocking carboxylation.• Antithrombotic effect of warfarin depends on a reduction in
the functional levels of factor X(t1/2 24hrs),prothrombin(t1/2 72hrs)
• Racemic mixture• Completely absorbed.• 97%bound to albumin.• Coagulation monitoring is essential,narrow Therapuetic
index.
Metabolism of warfarin
Warfarin
S isomerMore active
CYP2C9*2
Homozygosity 50-70% reduction
Heterozygosity25-30%
reduction
CYP2C9*3 VKORC1
A/Aheterozygotes -
25%
A/A homozygotes
50%
R isomer
CYP1A1CYP1A2CYP3A4
Warfarin name ….?
Wisconsin Alumni Research Foundation
+ the ending -arin indicating its link with coumarin. Dosing regimen Tait,Kovacs,Fennerty
• Flat nasal bridge ,• laryngomalacia,• pectus carinatum,• ventriculomegaly,• Agenesis ofcorpus
callosum,• stippled epihpysis
Trials of New anticoagulants
Clinical condition
Dabigatran Rivaroxaban Apixaban
Post op VTEProphylaxis(TKA)
RE-MODELRE MOBILIZE
RECORD 3,4 ADVANCE 1,2
Result Dabigatran>enoxaparin(36.4 vs 37.7%)
Rivaroxaban>enoxaparin(9.6 vs18.9%)
Apixaban>enoxaparin(15 vs24%)
Post opVTE prophylaxia (THA)
RE-NOVATE RECORD 1,2 ADVANCE 3
Result 6.0% vs 6.7% 1.1% vs 3.7% 1.4% vs 3.9%
AF RELY ROCKET AF AVEREOS(failed warfarin
ARISTOTLE(warfarin)
Acute VTE RECOVER EINSTEIN AMPLIFY EXT
Result 2.4% vs 2.1% 2.1 vs 3.0% 1.7% vs 8.8%
Medically ill MAGELLAN
Result Rivaroxaban >enoxa
Trials on edoxaban• 1.A randomized,dose ranging,warfarin controlled,phase 2 study
involving 1146 pts with AF showed that once daily doses of Edoxaban(60 mg or 30mg) were safer than twice daily doses.
Thromb Haemostat 2010;104:633-41
• 2.A phase 3 study involving 8292 patients with Acute Venous Thromboembolism showed that once daily Edoxaban at a dose of 60 mg (reduced to 30 mg in selected patients) was as effective as Warfarin for the prevention of recurrent symptomatic venous thromboembolism and associated with significant lower rate of bleeding.
NEJM2013;369:1406-15
AnticoagulantsDRUG TRADE
NAMETRIALS FDA
Approvalyear
Year of entry into market
Indications
WARFARIN COUMADIN YES 48$/yr AF,VTE,Prosthetic heart valves
NICOUMALONE ACITROM YES 41.50$/60 tabs
DABIGATRAN PRADAXA RELY YES(Oct,2010)
3000$/yr
VTE,AF
RIVAROXABAN XARELTO(BAYER)
ROCKET AF YES(Nov,2011)
725Rs/Tablet
VTE,AF
APIXABAN ELIQUIS ARISTOTLE YES(Dec,2012)
VTE,AF
EDOXABAN LIXIANA ENGAGE AF TIMI 48
NO (?2014)
Summary of new oral anticoagulants
• Broad therapeutic window• No need of frequent monitoring.• Dose to be adjusted in renal failure.• Caution with the use of Glycoprtoein P inhibitors.• Not to be used with glycoprotein Pinducers(rifamipicin)• Dabigatran causes acidity.• Apixaban in case of recent GI bleeding.• Not indicated in valvular AF.• Dabigatran,apixaban in pts with ischemic stroke on
warfarin.
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