ATS REF Prof

ATS
Basel
Sekundärprophylaxe nach
Schlaganfall
Stefan Engelter
26. April 2012
Stroke- Rezidivprävention
Prinzipien
ANTITROMBOTIKA
Übersicht
Aetiologie und „Number needed to treat“
OAK versus ASS/Clopidogrel
Neue Orale Antikoagulatien
Antikoagulationsbeginn
NASCET
Guidelines for Management of Ischemic Stroke and Transient Ischemic Attack 2008
Cerebrovasc Dis 2008;25:457-507
Guidelines for Management of Ischemic Stroke and Transient Ischemic Attack 2008
Cerebrovasc Dis 2008;25:457-507
Vorhofflimmern: Antikoagulation vs. Placebo
Relative Risikoreduktion
95% CI
AFASAK I
SPAF
BAATAF
CAFA
SPINAF
Alle Studien
RRR = 62 %
100%
50%
0
-50%
-100%
Hart RG et al. Ann Intern Med 1999;131:492-501
OAK versus ASS/Clopidogrel
100%
Primäre Outcomes
Antikoagulation
80%
Aspirin
Schlaganfälle
12%/J  4%/J
60%
Placebo
1J
2J
Lit.: EAFT Study Group, Lancet 1993;342:1255-62
Ereignisse
17%/J  8%/J
3J
100%
Primäre Outcomes
Antikoagulation
80%
Probleme der OAK:
• Langsamer Wirkungseintritt
Aspirin
Schlaganfälle
12%/J  4%/J
• Interaktionen (Medi, Diät)
• Enges therap. Fenster (INR 2-3)
60%
• Engmaschiges Monitoring (Labor)
Placebo
• Effekt individuell unbestimmt
1J
2J
Lit.: EAFT Study Group, Lancet 1993;342:1255-62
Ereignisse
17%/J  8%/J
3J
ACTIVE W: Orale Antikoagulation ist einer TcAggregationshemmer-Kombination überlegen!
Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events - Warfarin
Einschlusskriterien : dokumentiertes VHF + mind 1 RF für Hirnschlag:
Alter >75, Hypertonie, LVEF <45%, PAVK, D.mell (55-74j.), Anamnese mit Stroke, TIA
-30%
Primary
outcome:
composite
endpoint of
stroke,
non-CNS
systemic
embolus,
MI or
vascular
death
p=0.0003
-77%
p=0.005
(Primary outcome+major bleed)
Studie gestoppt nach medianem Verlauf 1.28 Jahre
ACTIVE Writing Group of the ACTIVE Investigators Lancet 2006;367:1903-12
ACTIVE A: ASS+Clopidogrel versus ASS-Monotherapie
Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events - Aspirin
Einschlusskriteriedokumentiertes VHF + mind 1 RF für Hirnschlag:
Alter >75, Hypertonie, LVEF <45%, PAVK, D.mell (55-74j.), Anamnese mit Stroke, TIA
Ablehnung der OAK durch Pat., oder KI
RR -28%
p<0.001
RR -3%
p=0.69
Primary
outcome:
composite
endpoint of
stroke,
non-CNS
systemic
embolus, MI or
vascular death
Signifikante Hirnschlagrisikoreduktion für Kombinationtherapie nach median 3.6Jahre
Connolly SJ, et al. N Engl J Med 2009;360:2066-78
Optimaler INR-Bereich bei nichtvalvulärem Vorhofflimmern
Relatives Risiko
Risiko für Blutung
10.0
Risiko für
Stroke
8.0
6.0
4.0
2.0
0.0
0. 0
1.0
2. 0
3.0
4.0
5.0
6.0
INR
(Lit: EM Hylek, NEJM 1996;335:540)
Warfarin in AF:
Time in therapeutic range
Warfarin in AF: SUBGROUPS
Neue Orale Antikoagulatien
Warum neue Antikoagulantien zur Prävention des
Hirnschlages bei Vorhofflimmern
• 
• 
• 
• 
Vitamin K Antagonisten sind wirksam
Werden noch immer zu wenig eingesetzt
„Time in therapeutic range“ unzureichend(?)
Einsatz durch Nebenwirkungen eingeschränkt: intrakranielle
Hämorrhagien, enges therapeutisches Fenster, Nahrungsmittel
und Medikamenteninteraktionen, individuelle Wirksamkeit/Dosis
nicht voraussehbar (CyP-Polymorphismen)
•  Alternativsubstanzen müssen mindestens die gleiche
Wirksamkeit mit einem tieferen Blutungsrisiko aufweisen
und eine einfache Behandlung gewährleisten
Neue orale Antikoagulantien
ESC De Caterina JACCS 2012
Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K
Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation
(ROCKET AF)
•  double-blind trial,
• 
• 
• 
• 
• 
14,264 patients with nonvalvular atrial
fibrillation at increased risk for stroke
rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin
designed to determine whether rivaroxaban was non-inferior to warfarin
primary end point of stroke or systemic embolism
published on August 10, 2011, at NEJM.org.
Rocket Results: Primary efficacy endpoint
Kaplan–Meier survival curve showing time to the primary endpoint (stroke or systemic embolism)
Cumulative event rate – stroke or
systemic embolism (%)
7
Event rates:
6
Prior stroke/TIA,
warfarin
1.7% vs. 2.2%/yr
5
RR 0.79
4
Prior stroke/TIA,
rivaroxaban
No prior stroke/TIA,
warfarin
3
No prior stroke/TIA,
rivaroxaban
2
1
0
0
6
Per protocol population, on-treatment
12
18
24
Months from randomization
30
Rocket:Efficacy analysis
Stroke or
systemic
embolism
Any stroke
Rivaroxaban
Warfarin
Events/100 pt- Events/100 ptyrs
yrs
1.09
1.69
2.26
2.60
No prior stroke or TIA
Prior stroke or TIA
Interaction
p-value
0.15
1.06
2.21
1.53
2.37
0.16
Haemorrhagic
stroke
0.17
0.35
0.41
0.47
0.22
Ischaemic or
unknown stroke
0.89
1.86
1.11
1.92
0.41
Disabling or
fatal stroke
0.45
1.15
0.88
1.31
0.07
Non-CNS
systemic
embolism
Any cause death
0.04
0.05
0.16
0.23
0.99
2.00
1.74
2.35
2.07
0.94
Vascular death
1.61
1.44
1.70
1.71
0.60
0.1
Per protocol population, on-treatment
Favours
rivaroxaban
1
Favours
warfarin
10
Rocket-AF Subgroup: Stroke/TIA
Rocket-AF Subgroup: Stroke/TIA-Pts
SAFETY
Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)
•  noninferiority trial
•  18,113 patients with fibrillation and a risk of stroke
•  blinded , fixed doses of dabigatran — 110 mg or 150 mg twice daily
— or, in an unblinded fashion, adjusted-dose warfarin
•  follow-up period 2.0 years
•  primary outcome: stroke or systemic embolism
Results: Time to first stroke or systemic embolism
Cumulative hazard rates
0.05
Warfarin
Dabigatran 110 mg BID
Dabigatran 150 mg BID
0.04
RR 0.90
(95% CI: 0.74–1.10)
P<0.001 (NI)
P=0.30 (Sup)
RRR
35%
0.03
0.02
Event rates:
0.01
RR 0.65
(95% CI: 0.52–0.81)
P<0.001 (NI)
P<0.001 (Sup)
1.69% vs. 1.53% vs. 1.11%
RR 0.91 resp. 0.66
0.00
0.0
0.5
1.0
1.5
2.0
2.5
Years
BID = twice daily; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2010;363:1875–6
24
Dabigatran etexilate 110 mg BID compared with warfarin for
stroke prevention in AF
Favours dabigatran
110 mg BID
Favours
warfarin
Stroke or
systemic embolism
Stroke
Hemorrhagic stroke
Ischaemic or
unspecified stroke
Non-disabling
stroke
Disabling or fatal
stroke
0.5
Error bars = 95% CI; BID = twice daily
1.0
1.5
2.0
Relative risk
Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6
25
Risk of stroke or systemic embolism
Non-inferiority Superiority
P-value
P-value
Dabigatran
110 mg BID
vs. warfarin
0.30
Margin = 1.46
<0.001
Dabigatran
150 mg BID
vs. warfarin
<0.001
0.50
0.75
1.00
1.25
<0.001
1.50
Hazard ratio
Error bars = 95% CI; BID = twice daily
Connolly SJ et al. N Engl J Med 2010;363:1875–6
26
RE-LY: subgroup with prior stroke or
TIA
• 
Diener HC et al: www.thelancet.com/neurology
online November 8, 2010 DOI:10.1016/S1474-4422(10)70274-X
RE-LY® in perspective
Meta-analysis of ischaemic stroke
or systemic embolism
Favours
warfarin
Warfarin vs.:
Favours
other treatment
Placebo
Low-dose warfarin
Aspirin
Aspirin + clopidogrel
Ximelagatran
Dabigatran 110 mg BID
Dabigatran 150 mg BID
0.0
0.5
1.0
Hazard ratio
Error bars = 95% CI; BID = twice daily
Adapted from Camm J. ESC 2009; oral presentation #182; Lip GYH & Edwards SJ. Thromb Res 2006;118:321–33
1.5
2.0
Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE)
• 
• 
• 
• 
apixaban 5 mg twice daily) compared to warfarin (target international
normalized ratio, 2.0 to 3.0)
18,201 patients with atrial fibrillation and at least one additional risk
factor for stroke.
primary outcome: ischemic or hemorrhagic stroke or systemic
embolism.
test for noninferiority, with key secondary objectives of testing for
superiority with respect to the primary outcome and to the rates of
major bleeding and death from any cause.
published online August 28, 2011
Apixaban versus Warfarin in Patients with Atrial Fibrillation
Event rates:
1.27%vs.1.60% /yr
RR: 0.66
Kaplan–Meier
Curves for the
Primary Efficacy
and
Safety Outcomes.
Granger CB et al. N Engl J Med 2011. DOI: 10.1056/
NEJMoa1107039
Efficacy Outcomes.
Granger CB et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1107039
Relative Risks of the Primary Efficacy and Safety Outcomes, According to Major Prespecified Subgroups
Granger CB et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1107039
Antikoagulationsbeginn
Efficacy and Safety of Anticoagulant Treatment in Acute Cardioembolic Stroke
A Meta-Analysis of Randomized Controlled Trials
Maurizio Paciaroni et al. Stroke 2007;38;423-430
<48 h
N = 4642 pts
significant
 in symptomatic intracranial bleedings: 2.5% vs 0.7%
odds ratio 2.89; 95% CI: 1.19 to 7.01, P=0.02
no sig. differences in recurrent ischem. stroke, death, disability
„In patients with AF and acute TIA, anticoagulation treatment should
begin as soon as possible in the absence of cerebral infarction or
haemorrhage.
ESC-Guideleines 2010; European Heart Journal (2010) 31, 2369–2429
Purroy Stroke 2007
38(12):3225
Apixaban: Excl. criteria:
•  „stroke within the previous 7 days“
N Engl J Med 2011;365:981-92
Dabigatran: Excl. criteria:
• „stroke within 14 days or severe stroke within 6 months before
screening “
N Engl J Med 2009;361:1139-51
Rivaroxaban: Excl. criteria:
•  Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive)
within 3 months or any stroke within 14 days before the randomization
visit
• Transient ischemic attack within 3 days before the randomization visit“
•  Fibrinolytics within 10 days before randomization
N Engl J Med 2011;365:883-91 (suppl. Material)
Neue orale Antikoagulantien im Vgl
Blutungen
Stroke/syst. Embol.
→Warfarin→
Intrakranielle Blutungen: Neuen Antikoagulation weniger als Warfarin
ESC De Caterina JACCS 2012
Zusammenfassung
•  Tc-Hemmer Standard nach atherothrombotischen Hirninfarkt
•  Bei Vorhofflimmern und Hirninfarkt/TIA: OAK
•  3 neue Antithrombotika zur Hirnschlagprävention bei VHF
•  Effekt gegenüber WF (Coumarine) jeweils vergleichbar bis besser
•  Im Vergleich zu WF (Coumarinen) weniger zerebrale Hämorrhagien
•  Dabigatran 2 x tgl., 2 mögliche Dosen (110, 150mg), Zulassung wird
unmittelbar erwartet
•  Rivaroxaban 1x tgl., eingeführt als Thromboseprophylaxe für chir.
Eingriffe, erweiterte Zulassung demnächst
•  Apixaban 2 Gaben tgl.,
Zulassungen CH pendent