EU API234 New Anticoagulants in Non-Valvular AF Efficacy and Safety RE-LY ROCKET-AF ARISTOTLE כנס האיגוד הישראלי לרפואה פנימית, יולי2013 ד" ר אבישי אליס, מנהל מחלקה פנימית ג, בי" ח בילינסון
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
New Anticoagulants in Non-Valvular AF Efficacy and Safety RE-LY ROCKET-AF ARISTOTLE
2013יולי , כנס האיגוד הישראלי לרפואה פנימית
ח בילינסון"בי, מנהל מחלקה פנימית ג, ר אבישי אליס"ד
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
ATRIAL FIBRILLATION = EMBOLI
RISK SCORING
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
ESC 2012 recommendations – Choice of anticoagulant
Adapted from Camm et al. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253.
Non-valvular AF Valvular AF*
<65 years & lone AF (including female) No
Assess risk of stroke (CHA2DS2-VASc score)
0 1 ≥2
Assess bleeding risk (HAS-BLED score) Consider patient values and preferences
No antithrombotic therapy
NOAC**
VKA
Yes
**NOAC should be considered instead of VKA (INR 2–3) for most patients with AF.
*Includes rheumatic valvular disease and
prosthetic valves
VKA
OAC therapy
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
The CHA2DS2-VASc scheme was adopted by the ESC to complement the CHADS2 scoring system
CHADS2 Score CHA2DS2-VASc Score Congestive heart failure 1 Congestive heart failure/left ventricular dysfunction 1
Hypertension 1 Hypertension 1
Aged ≥75 years 1 Aged ≥75 years 2
Diabetes mellitus 1 Diabetes mellitus 1
Stroke/TIA/TE 2 Stroke/TIA/TE 2
Maximum score 6 Vascular disease (prior MI, PAD, or aortic plaque) 1
Aged 65-74 years 1
Sex category (i.e. female gender) 1
Maximum score 9
Camm et al. Eur Heart J 2010;31:2369-429.
CHA2DS2-VASc: In patients with a CHADS2 score of 0-1, or When a more detailed stroke risk assessment is indicated
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
ESC 2012 recommendations – Choice of anticoagulant
Adapted from Camm et al. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253.
Non-valvular AF Valvular AF*
<65 years & lone AF (including female) No
Assess risk of stroke (CHA2DS2-VASc score)
0 1 ≥2
Assess bleeding risk (HAS-BLED score) Consider patient values and preferences
No antithrombotic therapy
NOAC**
VKA
Yes
**NOAC should be considered instead of VKA (INR 2–3) for most patients with AF.
*Includes rheumatic valvular disease and
prosthetic valves
VKA
OAC therapy
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
VKA therapy has several limitations
Considerable variability in dose-response
(genetic variations)1
Long half-life Slow onset and offset
of action1,2
Interactions with drugs and diet1
Narrow therapeutic window (INR range 2-3)1
Risk of stroke Risk of bleeding1
Convenience not optimal: Frequent coagulation
monitoring1
Frequent dose adjustments1
Issue in perioperative anticoagulation (bridging)2
1. Weitz et al. Eur J Haematol 2010;85 (Suppl 72);1-28. 2. Camm et al. Eur Heart J 2010;31:2369-429.
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
The risks of ischaemic stroke or intracranial bleed are high outside a narrow INR range
20
15
10
5
1
Odd
s Rat
io
1.0 INR 2.0 3.0 4.0 5.0 6.0 7.0 8.0
Intracranial bleeding risk
Ischaemic stroke risk
Ischaemic stroke risk Intracranial bleeding risk
Adapted from: Fuster et al. Circulation 2011;123:e269-e367. Hylek and Singer. Ann Intern Med 1994;120:897-902. Oden et al. Thromb Res 2006;117:493-9.
Adjusted odds-ratio for ischaemic stroke and intracranial bleeding in relation to intensity of anticoagulation
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
VKA therapy has several limitations
Considerable variability in dose-response
(genetic variations)1
Long half-life Slow onset and offset
of action1,2
Interactions with drugs and diet1
Narrow therapeutic window (INR range 2-3)1
Risk of stroke Risk of bleeding1
Convenience not optimal: Frequent coagulation
monitoring1
Frequent dose adjustments1
Issue in perioperative anticoagulation (bridging)2
1. Weitz et al. Eur J Haematol 2010;85 (Suppl 72);1-28. 2. Camm et al. Eur Heart J 2010;31:2369-429.
9
The INR for VKAs is often outside the therapeutic range: international study of anticoagulation management
Tim
e in
targ
et ra
nge
(%)
0
20
40
60
80
100
US Canada France Italy Spain
INR <2 INR 2–3 INR >3
Ansell J et al. J Thromb Thrombolysis 2007;23:83–91
The predominant vitamin K antagonist (VKA) in use was warfarin in the US, Canada and Italy; acenocoumarol in Spain; and fluindione in France; INR = international normalized ratio
Warfarin for Atrial Fibrillation Limitations Lead to Under-treatment
0
20
40
60
80
<55 55-64 65-74 75-84 ≥85
44%
58% 61% 57%
35%
Age (years)
War
farin
Use
in
Elig
ible
Pat
ient
s (%
) 55% Overall Use
Go A et al. Ann Intern Med 1999;131:927.
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
Patients stop taking warfarin over time
Age 40-64
Age 75-79
Age 65-69
Age 80-84
Age 70-74
Age 85+
Patient age
0
20
40
60
80
100
Patie
nts
(%)
0 2 4 6 Time (years after starting treatment)
1
Adapted from Gallagher et al. J Thromb Haemost 2008;6:1500-6
~30% of AF patients treated with warfarin discontinued within 1 year (from a total population of 41,910 AF patients in the UK General Practice Research Database
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings 12
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
NEW ORAL ANTICOAGULANTS
NOACS
13
Copyright ©2011 American Heart Association
Hankey, G. J. et al. Circulation 2011;123:1436-1450
Illustration showing the sites of action of new anticoagulants in the coagulation cascade
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
השוואה בין התכשירים
15
16 For medical non-promotional reactive use only
Clinical pharmacology of apixaban, rivaroxaban and dabigatran
Apixaban1 Rivaroxaban2 Dabigatran3
Mechanism of action Direct factor Xa inhibitor
Direct factor Xa inhibitor
Direct thrombin inhibitor
Absolute availability ~50% 80–100% ~6.5% Route of administration Oral Oral Oral
Pro-drug No No Yes Food effect No No No
Renal clearance ~27% ~33 % 85%
Mean half-life (t1/2)
~12 h
7–11 h ~12–14 h
Tmax 3-4 h 2–4 h 0.5–2 h
1. Apixaban SmPC June 2011 2. Rivaroxaban SmPC March 2011 3. Dabigatran SmPC August 2011
No head-to-head comparisons between apixaban, rivaroxaban and dabigatran have been performed in a randomised clinical trial setting. The information in this table is based on the SmPCs for apixaban, rivaroxaban and dabigatran. Please refer to the SmPCs for further information.
Phase III trials vs warfarin (aim INR 2.0-3.0)
RELY ROCKET ARISTOTLE Sample size 18,113 14,266 18,201
New treatment Dabigatran 110mg BID
Dabigatran 150mg BID
Rivaroxaban 20mg
QD
Apixaban 5mg
BID
Design Non-inferiority
PROBE
Non-inferiority
Double-blind
Non-inferiority
Double-blind
Patients AF + CHADS2 ≥ 1 AF + CHADS2 ≥ 2 AF + CHADS2 ≥ 1
Primary outcome Stroke (ischemic or hemorrhagic) or systemic embolism
Stroke (ischemic or hemorrhagic) or systemic embolism
Stroke (ischemic or hemorrhagic) or systemic embolism
Safety outcome Primary: Major Bleeding
Secondary: Major Bleeding + CRNM
Primary: Major Bleeding
Secondary: Major Bleeding + CRNM
Primary: Major Bleeding
Secondary: Major Bleeding + CRNM
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011; ENGAGE- AF Study Investigators. AHJ 2010
P
Superiority
P
Non-
inferiority
HR
(±CI)
Warfarin
N (%/yr)
Study
medication
N (%/yr)
Medication Study
0.34 <0.001 0.91
(0.74-1.11)
199
(1.69)
182
(1.53)
Dabigatran
110 mg BID
RE-LY
<0.001 <0.001 0,66
(0.53-0.82)
134
(1.11)
Dabigatran
150 mg BID
<0.001 0.88
(0.75-1.03)
306
(2.4*)
269
(2.1*)
Rivaroxaban
20 mg (15 mg) QD
ROCKET-AF
ITT
0.12 <0.001 0.79
0.66-0.96)
241
(2.2*)
188
(1.7*)
Per protocol,
As Treated
0.01 <0.001 0.79
(0.66-0.95)
265
(1.60)
212
(1.27)
Apixaban
5 mg (2.5 mg) BID
ARISTOTLE
Primary End-points – Stroke & Systemic Emboli
New antithrombotic therapies compared to warfarin Stroke or systemic embolism
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Favors NOAC Favors warfarin
New antithrombotic therapies compared to warfarin Stroke of ischemic or unknown origin
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Favors NOAC Favors warfarin
New antithrombotic therapies compared to warfarin All-cause mortality
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Favors NOAC Favors warfarin
New antithrombotic therapies compared to warfarin Major bleeding
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Favors NOAC Favors warfarin
New antithrombotic therapies compared to warfarin Gastrointestinal bleeding
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Favors NOAC Favors warfarin
New antithrombotic therapies compared to warfarin Intracranial hemorrhage
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Favors NOAC Favors warfarin
New antithrombotic therapies compared to warfarin Myocardial infarction
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Favors NOAC Favors warfarin
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings 26
Sebastian Sc, et.al, Circ Cardiovasc Qual Outcomes July (2012)
Patients with CHADS2 ≥3 Results:
New Anticoagulants in Atrial Fibrillation
New Anticoagulants in Atrial Fibrillation
New anticoagulants compared to warfarin in AF 2011
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Effet on outcome event D150 D110 Riva Apix
Superiority stroke √ √
Reduction hemorrhagic stroke √ √ √ √
Reduction mortality (√) √
Reduction major bleeding √ √
Increase gastrointestinal bleeding √ √
Increase myocardial infarction (√) (√)
Number of benefits compared to warfarin 3 2 1 4
מינון-?אחת ליום לעומת פעמיים*
?מה עושים אם שוכחים מנה*
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
144 150 156 162 1680
50
100
150
200
250
Api
xaba
n Pl
asm
a C
once
ntra
tion
(ng/
mL)
Time (hours)
The apixaban 5 mg BD regimen demonstrates a lower peak:trough ratio compared with apixaban 10 mg OD
Time (h)
Apix
aban
con
cent
ratio
n (n
g/m
L)
Mean plasma concentration following multiple oral doses
5 mg BD 10 mg OD
Frost et al. J Thromb Haemost 2007; 5 Supplement 2: P-M-664. Data on File API-001
EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings
Simulated plasma concentration-time profiles for apixaban 5 mg BID2
Time after the first dose (hours)
Apix
aban
con
cent
ratio
n (n
g/m
L)
50
100
150
200
150 160 170 180 190
Administered as intended
With a missed Dose administered 6 h before the next scheduled dose
With a missed dose administered along with the next scheduled dose
Without replacing the missed dose
If a dose is missed, patient should take apixaban immediately and then continue with twice daily intake as before1
1. Apixaban SmPC 2012 2. Data on file API-003
All new agents compared with warfarin
Advantages: • No monitoring
required • No variability • Fast onset of action • Fast offset • Lower IC hemorrhage
rates (about 50% lower for all)
Disadvantages: • No reversibility • No monitoring • Expensive (higher tier
by PBM) • Not once-daily in AM • Less clinical
experience • No data for cardiac
issues other than NVAF
Indirect comparison of dabigatran, rivaroxaban and apixaban for AF
* The available data indicate no significant difference in efficacy between dabigatran 150 mg and apixaban for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation. * However, apixaban is associated with less major bleeding than dabigatran 150 mg or rivaroxaban. * Rivaroxaban is less effective than dabigatran 150 mg in preventing stroke or systemic embolism. *Low renal clearance by apixaban.
Such an indirect comparison should be used only to generate hypotheses, which need to be tested in a dedicated randomized trial comparing the three drugs directly.
תודה