Requirements of new prophylactic agents
- At least as efficacious as current standard therapy
- At least as safe as current standard therapy
- Available for oral administration
- Require no monitoring
- No relevant interactions with food and common drugs
- Cost-effective
. in order to aid treatment compliance and avoid the serious consequences of thrombosis and bleeding
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–Some risk factors are not recognized → underestimating stroke risk
–Age is not a binary risk factor – rather, it is a continuum, with risk
increasing with each decade from the age of 65 years onwards
–CHADS2 classifies a substantial proportion of patients with AF as
being at ‘moderate risk’ of stroke → their stroke risk may be
underestimated → leading them to receive inadequate antithrombotic
therapy for stroke prevention
CHA2DS2-VASc:
–More reliably identifies patients at low risk, with validation studies
showing very few stroke events in patients categorized as being at low
risk of stroke
–Categorizes a small proportion of patients as intermediate risk
–Simplifies selection of patients for anticoagulation, helping to remove
much of the uncertainty regarding the optimal form of
thromboprophylaxis
Olesen JB et al. BMJ 2011;342:d124
Anticoagulation in AF
Stroke Risk Reductions
Hart R, et al. Ann Intern Med 1999;131:492
Warfarin Better Control Better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
100% 50% 0 -50% -100%
Aggregate
Reduction of stroke
RRR = 64%
Reduction of all
cause mortality
RRR = 26%
Warfarin compared with Aspirin for
stroke prevention in AF
Hart RG et al. Ann Intern Med 2007;146:857–67
100 –100 50 0 –50
AFASAK I
AFASAK II
EAFT
PATAF
Warfarin better Aspirin better
RRR 38%
(95% CI: 18–52%)
Chinese ATAFS
SPAF II
Age 75 yrs
Age >75 yrs
All trials
Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity;
†Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
STROKE RISK SCORE
CHA2DS2-VASc Risk Score Patient
CHF or LVEF < 40% 1 1
Hypertension 1
Age > 75 2
Diabetes 1
Stroke/TIA/
Thromboembolism
2
Vascular Disease 1
Age 65 - 74 1 1
Sex category (Female) 1 1
CHA2DS2-VASc = 3
- Lovenox 0,4 ml SC q12hrs
- Sintrom 1 mg daily (with adjusment of dosage
depending on the INR)
- Digoxin ½ mg IV and Digoxin ¼ mg daily.
- Zestril 5mg daily
- Spiromide ( Furosemide 20mg/Spironolactone
50mg) daily
MANAGEMENT
INR
0
0.5
1
1.5
2
2.5
3
0 5 10 15 20 25
INR
Days
FOLLOWING INR
2 months later:
- Presents to the CCU with sudden onset of right
sided weakness.
- Examination:
. Oriented
. Right side paralysis
. HR: 90/m, irregular
. BP: 120/70mmHg.
- INR: 1,3
EVOLUTION
Most strokes occurred in patients who
were under-anticoagulated
Association of stroke events with intensity of anticoagulation for
patients with AF treated with warfarin in major randomized trials
AFASAK SPINAF
IN
R
1.0
2.0
3.0
4.0
Target range
for study
ACC/AHA/ESC
recommended
INR (2.0–3.0)
BAATAF CAFA SPAF
INR at which stroke
event occurred
Levi M et al. Semin Thromb Haemost 2009;35:527–42
Routine coagulation
monitoring
Warfarin resistance
Numerous drug–drug
interactions
Numerous food–drug
interactions
INR = International normalized ratio; VKA = vitamin K antagonist.
Ansell J, et al. Chest 2008;133;160S-198S. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-137.
Nutescu EA, et al. Cardiol Clin 2008;26:169-187.
VKA therapy has
several limitations
that make it
difficult to use in
practice
Frequent dose
adjustments
Unpredictable
response
Slow onset/ offset
of action
Narrow therapeutic
window
(INR: 2.0–3.0)
Limitations of VKA therapy
VKA for AF
Limitations Lead to Inadequate Treatment
Samsa GP, et al. Arch Intern Med 2000;160:967.
INR above target
6%
Subtherapeutic INR
13%
INR in target range
15%
No warfarin
65%
Adequacy of Anticoagulation in
Patients with AFib in Primary Care Practice
Dose, Concentration, or Intensity
of Anticoagulation
T
h
ro
m
b
o
s
is
Safe Therapeutic
Range
Thrombosis Bleeding
The Ideal Anticoagulant
Wide Therapeutic Margin
• At least as efficacious as current standard therapy
• At least as safe as current standard therapy
• Available for oral administration
• Require no monitoring
• No relevant interactions with food and common drugs
• Cost-effective
... in order to aid treatment compliance and avoid the
serious consequences of thrombosis and bleeding
Requirements of new prophylactic agents
NEW ORAL ANTICOAGULANTS
?
Antithrombin
Fibrinogen
Factor II
(Prothrombin)
Fibrin
Factor IIa
(Thrombin)
Factor X
Factor IX Factor VII
Anti-FXa drugs
•Apixaban
•Edoxaban
•Rivaroxaban
•Betrixaban
Anti-FIIa drugs
•Dabigatran
•Ximelagatran
Factor Xa
VKA drugs
•Warfarin
•Sintrom
FVIIa
FIXa
New oral anticoagulants
Target sites
Features Warfarin New Agents
Onset Slow Rapid
Dosing Variable Fixed
Indications Same Same
Food effect Yes No
Drug interactions Yes Yes
Monitoring Yes No
Half-life Long Short
Antidote Yes No
Comparison of
New oral anticoagulants with warfarin
Rivaroxaban Apixaban Edoxaban
Renal Clearance
RE-LY
Open Label
Two Doses
Twice Daily
Renal Clearance
ROCKET-AF
Double Blind
Two Doses
Once Daily
Hepatic Clearance
ARISTOTLE
Double Blind
Two Doses
Twice Daily
Hepatic Clearance
ENGAGE
Double Blind
Two Doses
Once Daily
Dabigatran
Novel Anticoagulants
FIIa Inhibitor Fxa Inhibitor
New Oral Anticoagulants
Important Comparative Features + Clinical trials
Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14
Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22
Dabigatran
RE - LY
Apixaban
ARISTOTLE
Rivaroxaban
ROCKET - AF
Edoxaban
ENGAGE
Target
IIa
(thrombin)
Xa Xa Xa
Time to peak levels 2 h 1-3 h 2-4 h 1-2 h
Bioavailability 7% 66% 80% > 45%
Half-life 12-14h 8-15h 9-13h 8-10h
Renal elimination 80% 25% 33% 35%
Dose 150 mg b.i.d 5 mg b.i.d 20 mg o.d 30mg/60mg qd
Dose in renal
impairment
110 mg b.i.d 2.5 mg b.i.d 15 mg o.d (if
CrCl 30-49 ml/m)
Special
considerations
Dabigatran:
- Intestinal absorption is pH-
dependent and is reduced in patients
taking proton pump inhibitors
- Increased risk of bleeding in patients
takingverapamil/amiodarone/quinidine
/ketoconazole
Rivaroxaban:
- Higher levels expected in patients with
renal or hepatic failure
- Activity lower in fasted patients so
should be taken after food
New Oral Anticoagulants
Important Comparative Features + Clinical trials
RE-LY
R
Warfarin
(INR 2.0-3.0)
N = 6022
Dabigatran
Etexilate
110 mg bid
N = 6015
Dabigatran
Etexilate
150 mg bid
N = 6076
PROBE=Prospective Randomized
Open Trial with Blinded
Adjudication of Events
10 efficacy outcome = stroke or systemic embolism
10 safety outcome = major bleeding
Non-inferiority margin 1.46
open Blinded
Atrial fibrillation
≥1 Risk Factor
Absence of contra-indications
951 centers in 44 countries
0.50 0.75 1.00 1.25 1.50
Dabigatran 110 vs Warfarin
Dabigatran 150 vs Warfarin
Non-inferiority
P-value
< 0.001
< 0.001
Superiority
P-value
0.34
< 0.001
M
a
rg
in
=
1
.4
6
HR (95% CI)
RE-LY Efficacy (Dabigatran)
Stroke/Systemic Embolic Event
Connolly, et al. N Engl J Med
2009;361:1139-51
0.1 0.3 0.5 1.0 2.0
Dabigatran 110 mg Dabigatran 150 mg
Stroke/SEE
Ischemic Stroke
Hemorrhagic Stroke
0.91 (0.74-1.11)
0.66 (0.53-0.82)
1.11 (0.89-1.40)
0.76 (0.60-0.98)
0.31 (0.17-0.56)
0.26 (0.14-0.49)
Dabigatran Better Warfarin Better
RE-LY Efficacy (Dabigatran)
0.1 0.3 0.5 1.0 2.0
Major Bleed
ICH
GI Bleed
0.80 (0.69-0.93)
0.93 (0.81-1.07)
0.31 (0.20-0.47)
0.40 (0.27-0.60)
1.10 (0.86-1.41)
1.50 (1.19-1.89)
MI
1.29 (0.96-1.75)
1.27 (0.94-1.71)
Dabigatran Better Warfarin Better
Dabigatran 110 mg Dabigatran 150 mg
RE-LY Safety results
(Dabigatran)
Rivaroxaban Warfarin
Primary End point: 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 daily
15 mg for Cr Cl 30-49
Atrial Fibrillation
Randomize
Double blind / Double Dummy
(n = 14,266)
Risk Factors
• CHF
• Hypertension
• Age 75
• Diabetes
OR
• Stroke, TIA or Systemic
embolus
At least 2
required
Monthly Monitoring and adherence to
standard of care guidelines
Rivaroxaban Warfarin
Event
Rate
Event
Rate
HR
(95% CI)
P-value
On
Treatment
N = 14,143
1.70 2.15
0.79
(0.65, 0.95)
0.015
ITT
N = 14,171
2.12 2.42
0.88
(0.74, 1.03)
0.117
Rivaroxaban
better
Warfarin
better
Event Rates are per 100 patient-years
Based on Safety on Treatment or Intention-to-Treat through
Site Notification populations
0.5 1 2
Patel, et al. N Engl J Med 2011;365(10);883-891
ROCKET AF Efficacy
Stroke/Systemic Embolic Event
ROCKET AF Key Secondary Efficacy
Event
Rivaroxaban
(%/yr)
Warfarin
(%/yr)
Hazard Ratio
(95% CI)
P-
value
Ischemic Stroke 1.34 1.42 0.94 (0.75-1.17) 0.581
Hemorrhagic Stroke 0.26 0.44 0.59 (0.37-0.93) 0.024
MI 0.91 1.12 0.81 (0.63-1.06) 0.121
Total Mortality 1.87 2.21 0.85 (0.70-1.02) 0.073
Vascular Mortality 1.53 1.71 0.89 (0.73-1.10) 0.289
Patel, et al. N Engl J Med 2011; 365(10);883-891
ROCKET AF Safety
Event
Rivaroxaban
(%/yr)
Warfarin
(%/yr)
Hazard Ratio
(95% CI)
P-
value
Major and Clinically
Relevant Bleed
14.9 14.5 1.03 (0.96-1.11) 0.44
Major Bleed 3.6 3.4 1.04 (0.90-1.20) 0.58
Fatal Bleed 0.2 0.5 0.50 (0.31-0.79) 0.003
ICH 0.5 0.7 0.67 (0.47-0.93) 0.02
Patel, et al. N Engl J Med 2011; 365(10);883-891
Warfarin
(target INR 2-3)
Apixaban 5 mg oral twice daily
(2.5 mg bid in selected patients)
Primary outcome: stroke or systemic embolism
Hierarchical testing: non-inferiority for primary outcome,
superiority for primary outcome, major bleeding, death
Randomize
double blind,
double dummy
(n = 18,201)
Inclusion risk factors
Age ≥ 75 years
Prior stroke, TIA, or SE
HF or LVEF ≤ 40%
Diabetes mellitus
Hypertension
Warfarin/warfarin placebo adjusted by INR/sham INR
based on encrypted point-of-care testing device
Exclusion
Mechanical prosthetic valve
Severe renal insufficiency
Need for aspirin plus
thienopyridine
ARISTOTLE Trial Design: Apixaban
ARISTOTLE Efficacy: Apixaban
Granger CB, et al. NEJM 2011; 365:981-992
HR 0.79 (0.66–0.95)
P (non-inferiority) < 0.001
21% RRR
(1.27 %/yr )
(1.60 %/yr)
P (superiority) = 0.011
ARISTOTLE Efficacy Outcomes
Granger CB, et al. NEJM 2011; 365:981-992
Outcome
Apixaban
(N = 9120)
Warfarin
(N = 9081)
HR (95% CI) P Value
Event Rate
(%/yr)
Event
Rate
(%/yr)
Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011
Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012
Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42
Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) < 0.001
Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70
All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047
Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019
Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37
ARISTOTLE Safety End Points
Event
Apixaban
(%/yr)
Warfarin
(%/yr)
Hazard Ratio
(95% CI)
P-
value
ISTH Major Bleeding 2.13 3.09 0.69 (0.60-0.80)
<
0.001
ICH 0.33 0.80 0.42 (0.30-0.58)
<
0.001
GUSTO Severe 0.52 1.13 0.46 (0.35-0.60)
<
0.001
Gastrointestinal 0.76 0.86 0.89 (0.70-1.15) 0.37
Granger CB, et al. NEJM 2011; 365:981-992
ARISTOTLE: Apixaban
Renal Function
Hohnloser SH, et al. EHJ 2012 (epub August 29)
Baseline Cockcroft-Gault eGFR mL/min
A
n
n
u
a
liz
e
d
E
v
e
n
t
R
a
te
Stroke or SEE Major Bleeding
Low dose regimen
Edoxaban 30 mg qd
(n ≈ 7000)
Active Control
Warfarin
(n ≈ 7000)
High dose regimen
Edoxaban 60 mg qd
(n ≈ 7000)
AF on Electrical
Recording < 12 mo
Intended oral A/C
CHADS2 >2
N =
21,105
R
Randomization Stratified By
1. CHADS2 2-3 vs 4-6
2. Drug Clearance
Median Duration of Follow-up 24 Months
Primary Objective
Edoxaban: Therapeutically as Good as Warfarin
DOUBLE BLIND
DOUBLE DUMMY
1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38)
2º EP = Stroke or SEE or CV mortality
Safety EP’s = Major Bleeding, Hepatic Function
EVENT
DRIVEN
Ruff CR et al. Am Heart J 2010; 160:635-41
Phase III: Protocol Schema
RE-LY
(Dabigatran)
ARISTOTLE
(Apixaban)
ENGAGE AF-TIMI 48*
(Edoxaban)
ROCKET-AF
(Rivaroxaban)
# Enrolled 18,113 18,201 21,105 14,264
Age (yrs) 72 ± 9 70 [63-76] 72 [64-77] 73 [65-78]
Female 36% 35% 38% 40%
CHADS2 score ≥3 32% 30% 52% 87%
VKA naive 50% 43% 41% 38%
Paroxysmal AF 33% 15% 25% 18%
Prior stroke/TIA 20% 19% 18% / 12% 55%**
Diabetes 23% 25% 36% 40%
Prior CHF 32% 35% 56% 62%
Hypertension 79% 87% 90% 91%
* Preliminary data
** Includes prior systemic embolism
Connolly SJ et al. N Engl J Med 2009; 361:1139-51
Patel MR et al. N Engl J Med 2011; 365:883-91
Granger CB et al. N Engl J Med 2011; 365:981-92
Ruff CR et al. Am Heart J 2010; 160:635-41
Pivotal Atrial Fibrillation Trials
Baseline Characteristics
Drug
Dose (mg)
RE-LY ROCKET-AF ARISTOTLE
Dabigatran
110 bid 150 BID
Rivaroxaban
20 mg qd
Apixaban
5 mg bid
Stroke + SEE non-infer Superior
ITT cohort: non-infer.
On Rx cohort: Superior
Superior
ICH Superior Superior Superior Superior
Bleeding Lower similar similar Lower
Mortality similar P = 0.051 similar Superior: P = 0.047
Ischemic stroke similar Lower similar similar
Mean TTR 64% 55% 62%
Stopped drug 21% 23% 23%
WD consent 2.3% 8.7% 1.1%
TTR = time in therapeutic range
WD consent = withdrawal of consent, no further data available
Pivotal Atrial Fibrillation Trials
Results to Date
Efficacy of New Oral Anticoagulants
Favors NOACs Favors Warfarin
13%
55%
Hemorraghic Stroke
Ischemic & Unsp. Stroke
Stroke & SEE
The American Journal of Cardiology Volume 110, Issue 3 2012 453 - 460
Safety of New Oral Anticoagulants
GI
Major bleeding
Gastrointestinal bleeding
Incranial bleeding
The American Journal of Cardiology Volume 110, Issue 3 2012 453 - 460
51%
Favors NOACs Favors Warfarin
Despite continued use of warfarin, NOACs are
considered by many professional medical organizations
to be the “best option” for anticoagulation of SPAF
patients:
– ESC 2012 AF Update Guidelines
– ACCP 2012 Guidelines
– Canadian AF Guidelines
“Best Options” for Anticoagulation
The Consensus is Shifting
Atrial fibrillation
< 65 years and lone AF (including females)
Assess risk of stroke
CHA2DS2-VASc
Assess bleeding risk
(HAS-BLED score)
Consider patient values and
preferences
No antithrombotic
therapy
Oral anticoagulant therapy
NOAC VKA
0 1
No ( i.e non-valvular AF)
Yes
No
≥2
Valvular AF *
C
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