Edoxaban versus Warfarin
in Patients
with
Atrial Fibrillation
Effective ANticoaGulation
with
Factor XA next GEneration
in
Atrial Fibrillation –
Thrombolysis In
Myocardial Infarction 48...
Introduction
• Atrial Fibrillation (AF) is the most common type of arrhythmia.
• It is a supraventricular arrhythmia chara...
• Warfarin

has been the sole effective agent in preventing

thromboembolic complications in pts with AF,but with risk of
...
Background
• Edoxaban is a oral, reversible,direct factor Xa inhibitor, having
linear and predictable pharmacokinetic prof...
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

...
Inclusion criteria
Randomized and study drugs
• Patients were randomly assigned in a 1:1:1 ratio, to receive
warfarin, dose adjusted to achie...
Dose of edoxaban was halved in case …
• At the time of randomization or during the study if…

 Estimated CrCl <30 to 50 m...
P Glycoprotein inhibitors
• Permeability glycoprotein, abbreviated as P-gp or Pgp
• Also known as multidrug resistance pro...
Study end points
The primary efficacy end point
• Time to the first adjudicated stroke (ischemic or hemorrhagic)

• System...
Results
• Total of 21,105 pts underwent randomization.
• 21,026(99.6%) received the study drug.
• A total of 5330(25.3%) r...
Primary end point
EVENTS

WARFARIN
GROUP

HIGH DOSE
EDOXABAN

P VALUE LOW DOSE P VALUE
EDOXABAN

STROKE or
SYSTEMIC
EMBOLI...
Bleeding
OUTCOME

WARFARIN
(%of pts/yr)

HIGH DOSE
EDOXABAN

LOW DOSE
EDOXABAN

P
VALUE

MAJOR BLEEDING

524 (3.43%)

418 ...
Secondary and other efficacy
outcomes
• Rates of all three prespecified secondary composite
outcomes were significantly lo...
Discussion
• Both doses of edoxaban were non inferior to warfarin.
• High dose edoxaban more effective than warfarin.
• Ra...
Comparison of edoxaban regimens
HIGH DOSE EDOXABAN
vs
LOWDOSE EDOXABAN

Rate of stroke,systemic
embolic event
Reduction in...
Anticoagulants
Warfarin

Rivaroxaban

50yrs

Factor Xa
inhibitor

Rodent
poison

Edoxaban
Factor Xa
inhibitor

Dabigatran
...
Warfarin
• Water soluble VKA,initially developed as rodenticide.
• Inhibits synthesis of vitamin K dependent clotting fact...
Metabolism of warfarin
Warfarin

S isomer

R isomer

More active

CYP1A1

CYP2C9*2

CYP2C9*3

CYP1A2

VKORC1

CYP3A4

Homo...
Warfarin name ….?
Wisconsin Alumni Research Foundation
+ the ending -arin indicating its link with
coumarin.
Dosing regime...
•
•
•
•
•

Flat nasal bridge ,
laryngomalacia,
pectus carinatum,
ventriculomegaly,
Agenesis ofcorpus
callosum,
• stippled ...
Trials of New anticoagulants
Clinical condition

Dabigatran

Rivaroxaban

Apixaban

Post op VTE
Prophylaxis(TKA)

RE-MODEL...
Trials on edoxaban
• 1.A randomized,dose ranging,warfarin controlled,phase 2 study
involving 1146 pts with AF showed that ...
Anticoagulants
DRUG

TRADE
NAME

WARFARIN

COUMADIN

Year of Indications
entry
into
market
48$/yr

YES

NICOUMALONE ACITRO...
Summary of new oral
anticoagulants
•
•
•
•
•
•
•
•
•

Broad therapeutic window
No need of frequent monitoring.
Dose to be ...
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
THE ENGAGE AF TIMI 48 trial
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  • P GLYCOPRTN PIC
  • THE ENGAGE AF TIMI 48 trial

    1. 1. Edoxaban versus Warfarin in Patients with Atrial Fibrillation
    2. 2. Effective ANticoaGulation with Factor XA next GEneration in Atrial Fibrillation – Thrombolysis In Myocardial Infarction 48 (ENGAGE AF TIMI 48)
    3. 3. 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.
    4. 4. • 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.
    5. 5. 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.
    6. 6. Two dose regimens of once daily edoxaban with warfarin in patients with AF who were at moderate to high risk for stroke.
    7. 7. 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.
    8. 8. Inclusion criteria
    9. 9. 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.
    10. 10. 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 (verapamil or quinidine,dronedarone). inhibitors
    11. 11. P Glycoprotein inhibitors • Permeability glycoprotein, abbreviated as P-gp or Pgp • Also known as multidrug resistance protein 1 (MDR1) or ATPbinding 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
    12. 12. 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.
    13. 13. 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.
    14. 14. Primary end point EVENTS WARFARIN GROUP HIGH DOSE EDOXABAN P VALUE LOW DOSE P VALUE EDOXABAN STROKE or SYSTEMIC EMBOLISM 232 (1.50%/yr) 182 (1.18%/yr) P<0.001 P=0.02 253 (1.61%/yr) ANNUALIZED RATE (ITT) 1.80%/yr 1.57%/yr 2.04%/yr HEMORRHAGIC STROKE 0.47% 0.26% 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% P<0.001 0.16% P=0.005 P=0.44 <0.001
    15. 15. 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
    16. 16. Secondary and other efficacy outcomes • Rates of all three prespecified secondary composite outcomes were significantly lower with high dose edoxaban • Lower annualized rates of (2.74% vs 3.17%). CV death with edoxaban
    17. 17. 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.
    18. 18. Comparison of edoxaban regimens HIGH DOSE EDOXABAN vs LOWDOSE EDOXABAN Rate 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
    19. 19. Anticoagulants Warfarin Rivaroxaban 50yrs Factor Xa inhibitor Rodent poison Edoxaban Factor Xa inhibitor Dabigatran Apixaban Factor IIa inhibitor Factor xa inhibitor
    20. 20. 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.
    21. 21. Metabolism of warfarin Warfarin S isomer R isomer More active CYP1A1 CYP2C9*2 CYP2C9*3 CYP1A2 VKORC1 CYP3A4 Homozygosity 50-70% reduction Heterozygosity A/A 25-30% reduction heterozygotes 25% A/A homozygotes 50%
    22. 22. Warfarin name ….? Wisconsin Alumni Research Foundation + the ending -arin indicating its link with coumarin. Dosing regimen Tait,Kovacs,Fennerty
    23. 23. • • • • • Flat nasal bridge , laryngomalacia, pectus carinatum, ventriculomegaly, Agenesis ofcorpus callosum, • stippled epihpysis
    24. 24. Trials of New anticoagulants Clinical condition Dabigatran Rivaroxaban Apixaban Post op VTE Prophylaxis(TKA) RE-MODEL RE MOBILIZE RECORD 3,4 ADVANCE 1,2 Result Dabigatran>enoxap Rivaroxaban>enoxa arin(36.4 vs 37.7%) parin(9.6 vs18.9%) Apixaban>enoxapari n(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
    25. 25. 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
    26. 26. Anticoagulants DRUG TRADE NAME WARFARIN COUMADIN Year of Indications entry into market 48$/yr YES NICOUMALONE ACITROM FDA Approval year YES TRIALS 41.50$/ 60 tabs YES (Oct,2010) 3000$/y r VTE,AF 725Rs/ Tablet VTE,AF DABIGATRAN PRADAXA RELY RIVAROXABAN XARELTO (BAYER) ROCKET AF YES (Nov,2011) APIXABAN ELIQUIS ARISTOTLE YES (Dec,2012) EDOXABAN LIXIANA ENGAGE AF TIMI 48 NO (?2014) AF,VTE, Prosthetic heart valves VTE,AF
    27. 27. 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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