Stroke Prevention: using a new anticoagulant in everyday clinical practice Ahmad Hersi, MBBS, MSc, FRCPC Associate Professor of Cardiac Sciences
Outlines • • • • •
Warfarin efficacy and safety ASA new safety data Risk stratification schemas New anticoagulant Agents Real life experience with Dabigatran
AF is an independent risk factor for stroke and the attributable risk increases with age
Stroke Risk Attributableto AF
Framingham Significant increase with age p<0.01
% 25
23.5%
20 15 9.9% 10 5
1.5%
2.8%
0 50-59
60-69
70-79
80-89
Age (years)
Wolf et al. Stroke 1991;22:983-988.
3
Increased risk of death after stroke in patients with AF persists for up to 8 years
Mortality Annual mortality rate, %
60
50
Patients with AF Patients without AF
40 30 20
10 0 1
2
3
4
Years post-stroke Population-based study of 3530 patients with ischaemic stroke Marini C et al. Stroke 2005;36:1115â&#x20AC;&#x201C;9
5
6
7
8
Stroke survivors with AF have poorer outcomes Outcome measure
Patients with AF
Patients without AF
Initial stroke severity, SSS score*
30
38
Initial disability, BI score*
35
52
Length of hospital stay, d
50
40
In hospital mortality, %
33
17
Discharged to nursing home, %
19
14
Neurological outcome, SSS score*
46
50
Functional outcome, BI score*
67
78
*Lower scores are associated with a poorer prognosis SSS = Scandinavian Neurological Stroke Score; BI = Barthel Index
Jorgensen HS et al. Stroke 1996;27:1765â&#x20AC;&#x201C;9
Anticoagulation in Atrial Fibrillation Stroke Risk Reductions Warfarin Better
Control Better
AFASAK SPAF BAATAF CAFA SPINAF EAFT
Aggregate 100% Hart R, et al. Ann Intern Med 2007;146:857.
50%
0
-50%
-100%
Efficacy of Warfarin in Trials vs. Practice Stroke Risk Reductions Treatment Better
Treatment Worse
Warfarin vs. Placebo/Control
6 Trials n = 2,900
Warfarin vs. No anticoagulation
Patients Age >65 years n = 23,657
100%
Hart R, et al. Ann Intern Med 2007;146:857 Birman-Deych E. Stroke 2006; 37: 1070â&#x20AC;&#x201C;1074
50%
0
-50%
RE-LY Registry Oral anticoagulation use CHADS2 ≥ 2 North Am
OAC use (CHADS 65.1% 2 ≥ 2) % INR (2-3)
53.5
South Am
West Eur
44.8%* 63.5%
43.5
66.9
East Eur
Middle East
Africa
India
China
Asia
38.7%* 55.8%* 36.9%* 39.9%* 10.5 %* 43.6%*
59.1
46.8
39.5
33.9
ecardio.org, congress report 2011
36.1
38.4
ACTIVE-W outcomes by INR control Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range
“Bad” INR control
“Good” INR control
ASA + Clopidogrel
Warfarin
Stroke Outcome; TTR= time in therapeutic range Connolly et al. Circulation 2008; 118:2029-37
ACTIVE W:Major Bleeding and INR Control
RR = 0.68
0.04
0.04
RR = 1.55
P = 0.08
0.03
0.03
P = 0.027
OAC
0.02
0.02
C+A
0.01
C+A
0.0
0.01
OAC
0.0
Cumulative Hazard Rates
<65% INR in Range
0.05
Interaction P = 0.0006
0.05
ď&#x201A;ł 65% INR in Range
0.0
0.5
ACTIVE Writing Group: Lancet 2006;367:1903-1912
1.0
1.5
0.0
Years
0.5
1.0
1.5
Risk of bleeding with ASA vs OAC
Friberg l Eu Heart J Jan 2012
Risk of bleeding with ASA vs OAC
Friberg l Eu Heart J Jan 2012
Effect of ASA on Vascular and nonvascular outcomes : Meta-analysis of RCT
Seshasai 2012, Arch Inter Med
Effect of ASA on Vascular and nonvascular outcomes : Meta-analysis of RCT
Seshasai 2012, Arch Inter Med
The CHADS2 Index Score (points)
Prevalence (%)*
Congestive Heart failure Hypertension Age >75 years Diabetes mellitus Stroke or TIA
1 1 1 1 2
32 65 28 18 10
Moderate-High risk Low risk
>2 0-1
50-60 40-50
VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).
The CHA2DS2VASc Index Weight (points) Congestive heart failure or LVEF < 35% Hypertension Age >75 years Diabetes mellitus Stroke/TIA/systemic embolism Vascular Disease (MI/PAD/Aortic plaque) Age 65-74 years Sex category (female)
1 1 2 1 2 1 1 1
Moderate-High risk Low risk
>2 0-1
Lip GYH, Halperin JL. Am J Med 2010; 123: 484.
The CHA2DS2VASc Index
Summary • Warfarin losses 50% of its efficacy in real world setting. • 50% of eligible patients for Warfarin are not on the drug. • INR is sub-therapeutic in 50% of patients on Warfarin • ASA has similar bleeding risk as OAC
New Anticoagulant Agents
Novel Oral Anticoagulants in Advanced Development Pharmacological Properties
Feature
Dabigatran
Rivaroxaban
Apixaban
Target
IIa
Xa
Xa
Prodrug
Yes
No
No
Time to peak (h)
2
3
3
Half-life (h)
12-17
9-13
9-14
Renal excretion (%)
80
65
25
Antidote
None
None
None
WeitzJI. ACC Scientific Sessions, March 13, 2010. Gibson M. ESC Scientific Sessions, August 2011.
Novel Anticoagulants for SPAF • Dabigatran: RE-LY – N = 18,113 (951 centers, 44 countries) – Funding/Coordination: BI, PHRI – Enrollment 12/2005-12/2007, NEJM 9/2009 • Rivaroxaban: ROCKET-AF – N = 14,246 (1178 centers, 45 countries) – Funding/Coordination: J&J/Bayer, DCRI – Enrollment 12/2006-6/2009, NEJM 9/2011 • Apixaban: ARISTOTLE – N = 18,201 (1034 centers, 39 countries) – Funding/Coordination: Pfizer/BMS, DCRI – Enrollment 12/2006-4/2010, NEJM 9/2011
Study Conduct • Dabigatran: RE-LY – FU = 2 Years – Complete FU = 99.9% – TTR = 64%
• Rivaroxaban: ROCKET-AF – FU = 1.9 Years – Complete FU = 99.9% – TTR = 55%
• Apixaban: ARISTOTLE – FU = 1.8 Years – Complete FU = 97.9% – TTR = 62%
RE-LY Trial Randomized Evaluation of Long-term Anticoagulant Therapy with Dabigatran Etexilate Non-valvular AF + >1 stroke risk factor Open-label
Warfarin (INR 2.0-3.0) n = 6,022
n = 18,113
Blinded
Dabigatran 110 mg bid n = 6,015
Dabigatran 150 mg bid n = 6,076
Primary objective: noninferiority vs. warfarin Observation period: minimum 1, mean 2, maximum 3 years Primary endpoint: all stroke + systemic embolism Safety measure: bleeding during treatment Connolly SJ et al. N Engl J Med 2009; 361: 1139.
RE-LY Trial Primary Events All Strokes and Systemic Embolic Events
Event Rate (%/year)
p <0.001 (Superiority)
4 p <0.001 (Noninferiority)
3 2
1.69
1.53
1 0
Connolly SJ et al. N Engl J Med 2009; 361: 1139.
1.11
Warfarin Dabigatran 110 mg bid Dabigatran 150 mg bid
RE-LY Trial All Major Bleeding Hgb ď&#x20AC;¤ >2 g/dl or Transfusion >2 units or Critical Site
Event Rate (%/year)
p = NS p = 0.002
Connolly SJ et al. N Engl J Med 2009; 361: 1139.
p = 0.04
RE-LY Trial Hemorrhagic Stroke Events Intracerebral hemorrhages Warfarin Dabigatran 110 mg bid Dabigatran 150 mg bid
Event Rate (%/year)
p <0.001
1 0.8 0.6 0.4
p <0.001
0.38
0.2 0
Connolly SJ et al. N Engl J Med 2009; 361: 1139.
0.10
0.12
RE-LY Trial All-Cause Mortality p = 0.047
Warfarin Dabigatran 110 mg bid Dabigatran 150 mg bid
Event Rate (%/year)
p = NS
5
4.13
4 3 2 1 0
Connolly SJ et al. N Engl J Med 2009; 361: 1139.
3.74
3.63
ROCKET-AF
Risk Factors
• CHF • Hypertension At least 2 or 3 required* • Age 75 • Diabetes OR • Stroke, TIA or Systemic embolus
Atrial Fibrillation Rivaroxaban 20 mg daily 15 mg for Cr Cl 30-49 ml/min
Randomize Double Blind / Double Dummy (n ~ 14,000)
Warfarin INR target - 2.5 (2.0-3.0 inclusive)
Monthly Monitoring Adherence to standard of care guidelines
Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
Mahaffey K N Engl J Med 2011
ROCKET-AF: Stroke/ SE HR 0.79 (95% CI 0.66-0.96) P<0.001
Mahaffey K N Engl J Med 2011
ROCKET-A F: Major Bleed
Mahaffey K N Engl J Med 2011
ROCKET AF: ICH
Mahaffey K N Engl J Med 2011
ARISTOTLE
ARISTOTLE
Risk Factors
• CHF • Hypertension • Age 75 • Diabetes OR • Stroke, TIA or Systemic embolus
Atrial Fibrillation Apixaban 5 mg BID
Randomize Double Blind / Double Dummy (n ~ 18201)
Warfarin INR target - 2.5 (2.0-3.0 inclusive)
Monthly Monitoring Adherence to standard of care guidelines
Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
At least 1 required*
ARISTOTLE: Stroke/SE HR 0.79 (0.66-0.95) P<0.01
Granger et al N Engl J Med , Sep 2011
ARISTOTLE: Stroke Ischemic P=0.42 Hemorrhagic P <0.001
ARISTOTLE: Major Bleed
Rates of Ischemic Stroke Comparisons to Warfarin RE-LY
Event Rate (%/year)
HR
p (ITT Analysis)
Dabigatran, 110 mg bid
1.34
1.20
0.35
Dabigatran, 150 mg bid
0.92
0.76
0.03
Warfarin
1.20
ROCKET-AF
Event Rate (%/year)
HR
p (ITT Analysis)
Rivaroxaban, 20 mg qd
1.62
0.99
0.92
Warfarin
1.64
ARISTOTLE
Event Rate (%/year)
HR
p (ITT Analysis)
Apixaban, 5 mg bid
0.97
0.92
0.42
Warfarin
1.05
Rates of Major Bleeding Comparisons to Warfarin RE-LY
Event Rate (%/year)
HR
p (ITT Analysis)
Dabigatran, 110 mg bid
2.71
0.80
0.003
Dabigatran, 150 mg bid
3.11
0.93
0.31
Warfarin
3.36
ROCKET-AF
Event Rate (%/year)
HR
p (OT Analysis)
Rivaroxaban, 20 mg qd
3.60
0.92
0.58
Warfarin
3.45
ARISTOTLE
Event Rate (%/year)
HR
p (ITT Analysis)
Apixaban, 5 mg bid
2.13
0.69
0.001
Warfarin
3.09
All-Cause Mortality Rates Comparisons to Warfarin RE-LY
Event Rate (%/year)
HR
p (ITT Analysis)
Dabigatran, 110 mg bid
3.75
0.91
0.35
Dabigatran, 150 mg bid
3.64
0.88
0.051
Warfarin
4.13
ROCKET-AF
Event Rate (%/year)
HR
p (ITT Analysis)
Rivaroxaban, 20 mg qd
4.52
0.92
0.152
Warfarin
4.91
ARISTOTLE
Event Rate (%/year)
HR
p (ITT Analysis)
Apixaban, 5 mg bid
3.52
0.89
0.01
Warfarin
3.94
Rates of ICH Event
HR
P-value
Dabigatran 110 150 Warfarin
0.23 0.32 0.74
0.31 0.40
0.001 0.001
Rivaroxabn Warfarin
0.5 0.7
0.67
0.02
Apixaban Warfarin
0.33 0.8
0.42
<0.001
Meta-anlaysis of new oral anticoagulants Am J Cardio 2012;April 24 Miller C et al
STROKE/SE
ISCHEMIC STROKE
HEMORRHAGIC STROKE
Meta-anlaysis of new oral anticoagulants Am J Cardio 2012;April 24 Miller C et al
Major bleeding
ICH
GI bleeding
â&#x20AC;˘ Clinical Practice Guidelines
European CPG 2012
European CPG 2012
European CPG 2012
Canadian Cardiovascular Society AF Guidelines Recommendations 2012 UPDATE â&#x20AC;˘ We recommend that all patients with AF or AFL (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke (e.g., CHADS2) and for the risk of bleeding (e.g., HAS-BLED), and that most patients should receive either an oral anticoagulant or ASA. (Strong Recommendation, High Quality Evidence)
â&#x20AC;˘ We suggest, that when OAC therapy is indicated, most patients should receive dabigatran or rivaroxaban or apixaban* in preference to warfarin. (Conditional Recommendation, High Quality Evidence) *Once approved by Health Canada.
Canadian Cardiovascular Society AF Guidelines Recommendations 2012 UPDATE
â&#x20AC;˘ Values and Preferences: This recommendation places a relatively high value on comparisons to warfarin showing that dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy for stroke prevention; dabigatran and rivaroxaban no more major bleeding and apixaban has less; dabigatran, rivaroxaban, and apixaban have less intracranial haemorrhage; and all three new OACs are much simpler to use.
Canadian Cardiovascular Society AF Guidelines Recommendations 2012 UPDATE
â&#x20AC;˘ The recommendation places less value on these features of warfarin: long experience with clinical use, availability of a specific antidote and a simple and standardized test for intensity of anticoagulant effect. The preference for one of the new OACs over warfarin is less marked among patients already receiving warfarin with stable INRs and no bleeding complications.
Conclusions • ASA has a bleeding risk similar to OAC • Female < 65 years with no other risk factor should not receive OAC • Dabigatran and Apxiban have a greater efficacy than Warfarin. • Rivaroxaban has similar efficacy to warfarin
Thank you