ATS REF Prof
Transcrição
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