ATS Basel Sekundärprophylaxe nach Schlaganfall. Stefan Engelter 26. April 2012

Transkript

1 ATS Basel Sekundärprophylaxe nach Schlaganfall Stefan Engelter 26. April 2012

2 Stroke- Rezidivprävention Prinzipien ANTITROMBOTIKA

3 Übersicht Aetiologie und Number needed to treat OAK versus ASS/Clopidogrel Neue Orale Antikoagulatien Antikoagulationsbeginn

4 NASCET Guidelines for Management of Ischemic Stroke and Transient Ischemic Attack 2008 Cerebrovasc Dis 2008;25:

5 Guidelines for Management of Ischemic Stroke and Transient Ischemic Attack 2008 Cerebrovasc Dis 2008;25:

6 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:

7 OAK versus ASS/Clopidogrel

8 100% 80% Antikoagulation Aspirin Primäre Outcomes Ereignisse 17%/J 8%/J Schlaganfälle 12%/J 4%/J 60% Placebo 1 J 2 J 3 J Lit.: EAFT Study Group, Lancet 1993;342:

9 100% 80% 60% Probleme der OAK: Langsamer Wirkungseintritt Antikoagulation Aspirin Interaktionen (Medi, Diät) Enges therap. Fenster (INR 2-3) Engmaschiges Monitoring (Labor) Effekt individuell unbestimmt Placebo Primäre Outcomes Ereignisse 17%/J 8%/J Schlaganfälle 12%/J 4%/J 1 J 2 J 3 J Lit.: EAFT Study Group, Lancet 1993;342:

10 ACTIVE W: Orale Antikoagulation ist einer Tc- Aggregationshemmer-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% p= % p=0.005 Primary outcome: composite endpoint of stroke, non-cns systemic embolus, MI or vascular death (Primary outcome+major bleed) Studie gestoppt nach medianem Verlauf 1.28 Jahre ACTIVE Writing Group of the ACTIVE Investigators Lancet 2006;367:

11 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:

12 Optimaler INR-Bereich bei nichtvalvulärem Vorhofflimmern Relatives Risiko Risiko für Stroke Risiko für Blutung INR (Lit: EM Hylek, NEJM 1996;335:540)

13 Warfarin in AF: Time in therapeutic range

14 Warfarin in AF: SUBGROUPS

15 Neue Orale Antikoagulatien

16 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

17 Neue orale Antikoagulantien ESC De Caterina JACCS 2012

18 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.

19 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 (%) Event rates: 1.7% vs. 2.2%/yr RR 0.79 Prior stroke/tia, warfarin Prior stroke/tia, rivaroxaban No prior stroke/tia, warfarin No prior stroke/tia, rivaroxaban Months from randomization Per protocol population, on-treatment

20 Rocket:Efficacy analysis Stroke or systemic embolism Rivaroxaban Events/100 ptyrs Any stroke Warfarin Events/100 ptyrs No prior stroke or TIA Prior stroke or TIA Interaction p-value Haemorrhagic stroke Ischaemic or unknown stroke Disabling or fatal stroke Non-CNS systemic embolism Any cause death Vascular death Per protocol population, on-treatment Favours 0.1 Favours rivaroxaban 1 10 warfarin

21 Rocket-AF Subgroup: Stroke/TIA

22 Rocket-AF Subgroup: Stroke/TIA-Pts SAFETY

23 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

24 Results: Time to first stroke or systemic embolism Cumulative hazard rates Warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID RR 0.90 (95% CI: ) P<0.001 (NI) P=0.30 (Sup) Event rates: RR 0.65 (95% CI: ) P<0.001 (NI) P<0.001 (Sup) 1.69% vs. 1.53% vs. 1.11% RRR 35% 0.00 RR 0.91 resp 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:

25 Dabigatran etexilate 110 mg BID compared with warfarin for stroke prevention in AF Stroke or systemic embolism Favours dabigatran 110 mg BID Favours warfarin Stroke Hemorrhagic stroke Ischaemic or unspecified stroke Non-disabling stroke Disabling or fatal stroke Error bars = 95% CI; BID = twice daily Relative risk Connolly SJ et al. N Engl J Med 2009;361: ; Connolly SJ et al. N Engl J Med 2010;363:

26 Risk of stroke or systemic embolism Non-inferiority P-value Superiority P-value Dabigatran 110 mg BID vs. warfarin Dabigatran 150 mg BID vs. warfarin Margin = 1.46 <0.001 < <0.001 Error bars = 95% CI; BID = twice daily Hazard ratio Connolly SJ et al. N Engl J Med 2010;363:

27 RE-LY: subgroup with prior stroke or TIA Diener HC et al: online November 8, 2010 DOI: /S (10)70274-X

28 RE-LY in perspective Warfarin vs.: Meta-analysis of ischaemic stroke or systemic embolism Favours warfarin Favours other treatment Placebo Low-dose warfarin Aspirin Aspirin + clopidogrel Ximelagatran Dabigatran 110 mg BID Dabigatran 150 mg BID 0.0 Error bars = 95% CI; BID = twice daily Hazard ratio 2.0 Adapted from Camm J. ESC 2009; oral presentation #182; Lip GYH & Edwards SJ. Thromb Res 2006;118:321 33

29 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

30 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 DOI: / NEJMoa

31 Efficacy Outcomes. Granger CB et al. N Engl J Med DOI: /NEJMoa

32 Relative Risks of the Primary Efficacy and Safety Outcomes, According to Major Prespecified Subgroups Granger CB et al. N Engl J Med DOI: /NEJMoa

33 Antikoagulationsbeginn

34 Efficacy and Safety of Anticoagulant Treatment in Acute Cardioembolic Stroke A Meta-Analysis of Randomized Controlled Trials Maurizio Paciaroni et al. Stroke 2007;38; <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

35 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,

36 Purroy Stroke (12):3225

37 Apixaban: Excl. criteria: stroke within the previous 7 days N Engl J Med 2011;365: Dabigatran: Excl. criteria: stroke within 14 days or severe stroke within 6 months before screening N Engl J Med 2009;361: 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: (suppl. Material)

38 Neue orale Antikoagulantien im Vgl Blutungen Stroke/syst. Embol. Warfarin Intrakranielle Blutungen: Neuen Antikoagulation weniger als Warfarin ESC De Caterina JACCS 2012

39 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