INDICE

MODIFICHE 2

SCOPO 2

CAMPO DI APPLICAZIONE 2

DOCUMENTI DI RIFERIMENTO 2

CONTENUTO 3

TERAPIE DI RIPERFUSIONE NELL’ICTUS ISCHEMICO ACUTO 3

PROCEDURA PER IL TRATTAMENTO TROMBOLITICO ENDOVENOSO E INTRARATERIOSO 6

TROMBOLISI EV STANDARD 6

TRATTAMENTO IN CASO DICONTROINDICAZIONI A TROMBOLISI EV 8

TROMBOLISI IN PAZIENTI CON ICTUS NON DATABILE O RISVEGLIO 13

TRATTAMENTO TROMBOLITICO IN PAZIENTI DI ETA’ SUPERIORE 80 ANNI 14

TRATTAMENTO RESCUE 16

ALLEGATI 18

Documento redatto da:

Dr.ssa Xxxxxxxx Xxxxxx - Stroke Unit Clinica Neurologica Dr.ssa Xxxxxx Xxxxxxxxx - Stroke Unit Clinica Neurologica Dr.ssa Xxxxxxxxx Xxxxxxx - Stroke Unit Clinica Neurologica Xxxx. X. Xxxxxxxx – Direttore Clinica Neurologica

Dr.ssa Xxxxxxx Xxxxxxx - Stroke Unit Clinica Neurologica Dr. Xxxxxx Xxxx - Stroke Unit Clinica Neurologica

Dr.ssa Xxxxxxxx Xxxxxxxx - U.O. Neuroradiologia Dr. Xxxxxxxx Xxxxxxx - U.O. Neuroradiologia

Dr. Xxxxxxx Xxxxxxx - U.O. Neuroradiologia Dr. Xxxx Xxxxxxxx - U.O. Neuroradiologia

Dr. Xxxxxxxxx Xxxxxxxx - Dipartimento Emergenza Urgenza Dr. Xxxxx Xxxxxxx - Dipartimento Emergenza Urgenza

Dr. Xxxxxxxx Xxxxxxx - Dipartimento Emergenza Urgenza Dr. Xxxxxxx Xxxxxx - U.O.Neurorianimazione

Dr. Xxxxxx Xxxxxx - U.O.Neurorianimazione Dr.ssa Xxxxxx Xxxxxxx - U.O.Neurorianimazione

Verifica

Approvazione

Emissione

Data di emissione 22/11/2011

Direttore Unità Operativa

Prof. Xxxxx Xxxxxx Xxxxxxxx

Direttore Unità Operativa

Prof. Xxxxx Xxxxxx Xxxxxxxx

Referente Accreditamento e Qualità Unità Operativa

Dr.ssa Xxxxxxx Xxxxxxx

MODIFICHE

Rev.	Approvazione		Pagine Modificate	Tipo - natura della modifica
Rev.	Data	Visto	Pagine Modificate	Tipo - natura della modifica
0				Prima emissione

SCOPO

Il presente protocollo definisce i criteri e le modalità operative per la gestione dei pazienti candidati al trattamento trombolitico alla luce delle più recenti evidenze scientifiche e degli studi attualmente in corso presso l’U.O. di Neurologia.

CAMPO DI APPLICAZIONE

Il protocollo si applica ogni qualvolta sia identificato un paziente eleggibile (secondo i criteri definiti nel documento) al trattamento trombolitico presso il centro di riferimento provinciale.

DOCUMENTI DI RIFERIMENTO

1. Xxxxx W, Xxxxx M, Xxxxxxx E, Xxxxxxx M, Xxxxxxx A, Xxxxxxxx D, Xxxxxx V, Xxxx KR, Xxxxxxxx Z, Xxxxxxx T, Schneider D, xxx Xxxxxx R, Xxxxxxxx N, Xxxx X, for the ECASS Investigators. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New Engl J Med 2008;359:1317-29.

2. Xxxxxx P et al. Indications for the performance of intracranial endovascular neurointerventional procedures. A scientific statement from the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Interdisciplinary Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. J NeuroIntervent Surg 2010;2:177e188. doi:10.1161/circulationaha.109.192217

3. The IMS Study Investigators Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke 2004, 35(4):904–91

4. IMS II Trial Investigators: The Interventional Management of Stroke (IMS) II Study. Stroke 38 (7):2127–2135

5. Xxxxxxxx HM, Xxxxxxxx KC et al. Is Intra-arterial thrombolysis safe after full-dose intravenous recombinant tissue plasminogen activator for acute ischemic stroke? Stroke 2007;38(1):80-84

Nell’Allegato 1 sono riportate le ulteriori voci bibliografiche su cui si basa questo protocollo.

CONTENUTO

TERAPIE DI RIPERFUSIONE NELL’ICTUS ISCHEMICO ACUTO

Gli eventi tromboembolici rappresentano la causa principale di ictus ischemico acuto. Le strategie di riperfusione si focalizzano sul tentativo di rimozione o disgregazione del trombo/embolo con l’obiettivo di ristabilire un adeguato flusso nel territorio vascolare ipoperfuso, ma ancora vitale (penombra). Ripristinare il flusso ematico entro una determinata finestra temporale a livello della penombra ischemica si traduce nella riduzione delle dimensioni finali del “core” ischemico e quindi in un miglioramento dell’esito clinico del paziente. Negli ultimi 10-15 anni sono stati pubblicati una serie di studi che dimostrano che una precoce ricanalizzazione del vaso ostruito è il fattore predittivo modificabile più importante dell’esito del paziente (Figura 1, manca fonte bibliografica vicino a figura).

Al momento sono in xxxxx xxxxx xx xxxxxxxxxxxx xxxxxxxxxx xxxxxxxxxx xxxxx xxxxxxxxxx xxxxxxxxxxxxx (xxx cui lo studio italiano SYNTHESIS EXPANSION), non essendo noto quale sia l’approccio più efficace nei pazienti con ictus ischemico acuto. Attualmente l’unico trattamento di ricanalizzazione approvato nell’ictus ischemico acuto è la trombolisi endovenosa con rtPA entro le 3 ore dall’insorgenza della sintomatologia, con recente estensione alle 4,5 ore in base allo studio ECASS III (1). Le linee guida americane sul trattamento endovascolare nei pazienti con ictus ischemico acuto indicano la trombolisi intra-arteriosa come possibilità terapeutica in pazienti selezionati con ictus maggiore e occlusione dell’arteria cerebrale media entro le 6 ore all’insorgenza della sintomatologia (classe I, livello di evidenza B). Le stesse linee guida indicano la possibilità di trombolisi intra-arteriosa in pazienti con controindicazioni alla terapia endovenosa come ad esempio un recente intervento chirurgico (classe II, livello di evidenza C). La possibilità di trombolisi intra-arteriosa non deve però precludere nei pazienti eleggibili la terapia endovenosa (2). Nonostante l’efficacia clinica del trattamento trombolitico endovenoso (ev) sia stata provata in numerosi studi randomizzati, tuttora circa il 50% dei pazienti che subiscono un ictus ischemico muore o rimane disabile. Pazienti con deficit neurologici maggiori, età avanzata e una mancata ricanalizzazione dopo terapia fibrinolitica presentano un esito clinico meno favorevole. Confrontando, mediante valutazione angiografica, il grado di ricanalizzazione vascolare ottenuto dopo terapia fibrinolitica endovenosa con l’esito clinico uno studio ha evidenziato che il 74% dei pazienti in cui si era ottenuta un’adeguata ricanalizzazione presentavano un buon esito clinico, a differenza del 36% dei pazienti in cui non si otteneva alcuna ricanalizzazione del vaso ostruito. Alcuni studi hanno dimostrato che la terapia fibrinolitica endovenosa con rt-PA consente di ottenere un’adeguata rivascolarizzazione nel 30-50% dei casi, con percentuali di ricanalizzazione ancora inferiori nel caso di occlusione di vasi prossimali di calibro maggiore. Controlli angiografici hanno dimostrato un tasso di ricanalizzazione post-fibrinolisi ev di appena il 10% nei casi di occlusione della porzione intracranica dell’arteria carotide interna (ICA) e di un 25% nei casi che coinvolgevano il tratto prossimale dell’arteria cerebrale media (M1). Inoltre i casi di riocclusione post-ricanalizzazione parziale raggiungono una percentuale del 34%. Questi dati hanno pertanto incentivato la ricerca di nuovi approcci e strategie di ricanalizzazione, quali procedure intra- arteriose, ultrasound-enhanced thrombolysis (sonotrombolisi), nuovi agenti fibrinolitici.

Procedure di emergenza nel trattamento dell’ictus ischemico (rescue e bridging). Per migliorare l’efficacia della terapia trombolitica, prevalentemente in pazienti con NIHSS (NIH

Stroke Scale) ≥ 10, spesso associato all’occlusione di vasi prossimali, è spesso necessario ricorrere ad approcci di ricanalizzazione multimodali. Infatti le procedure endovascolari, sia di tipo meccanico che la trombolisi intra-arteriosa, presentano migliori risultati in termini di ricanalizzazione rispetto alla trombolisi endovenosa. Tuttavia la loro reale efficacia clinica può essere controbilanciata dal ritardo nel trattamento che questi sistemi possono comportare.

La combinazione della trombolisi endovenosa e intra-arteriosa (bridging) combina la facilità e rapidità di utilizzo propri della fibrinolisi ev con la maggior efficacia in termini di rivascolarizzazione della fibrinolisi intra-arteriosa o della trombectomia meccanica endovascolare. Gli studi randomizzati più importanti che hanno valutato un approccio multimodale combinato tra la fibrinolisi ev e la fibrinolisi ia sono stati l’Interventional Management of Stroke (IMS) study e l’IMS II. (3,4) I pazienti con ictus ischemico acuto sono stati trattati, entro 3 ore dall’insorgenza dei sintomi, con trombolisi ev a 2/3 della dose normalmente indicata (0.6 mg/kg, dose massima 60 mg da somministrare nell’arco di 30 minuti), cui si è aggiunto un successivo approccio intra-arterioso con somministrazione locale di rt-PA. In entrambi gli studi la percentuale di eventi emorragici post- trattamento coincideva sostanzialmente con i risultati ottenuti nel NINDS stroke trial, mentre i pazienti trattati con approccio multimodale presentavano un esito clinico a 3 mesi significativamente migliore dei pazienti del NINDS trattati solo con rt-PA ev. Un ulteriore studio randomizzato multicentrico di fase 3, l’IMS III, è tuttora in svolgimento; il suo obiettivo è quello di valutare se un approccio combinato endovenoso/intra-arterioso determini una maggiore percentuale di rivascolarizzazione e un miglior esito clinico rispetto alla terapia trombolitica endovenosa standard iniziata entro le 3 ore dall’insorgenza di un ictus ischemico acuto. L’approccio multimodale consiste nella somministrazione di 2/3 della dose di rt-PA ev nell’arco di 40 minuti, seguiti da un trattamento endovascolare di fibrinolisi con somministrazione locale di rt-PA o di trombectomia con l’utilizzo di dispositivi meccanici. Nonostante gli studi appena menzionati prevedano la somministrazione ev di 2/3 della dose di rt-PA normalmente somministrata, esistono numerose evidenze cliniche che dimostrano la sicurezza di un approccio multimodale anche con dose piena (0,9 mg/kg) di rt-PA ev (trattamento “rescue”) (5).

La Consensus Conference del Karolinska Institute del 2010, in collaborazione con l’European Stroke Organization ha stabilito l’uso non routinario delle procedure di rivascolarizzazione intra- arteriosa solo nell’ambito di trials clinici e di protocolli locali con inserimento dei dati in registri (allegato 1).

Figura1

PROCEDURA PER IL TRATTAMENTO TROMBOLITICO ENDOVENOSO E INTRARATERIOSO

SCENARIO 1

TROMBOLISI EV STANDARD

0-4.5 ore dall’esordio

età 18-80 (inclusi)

La procedura ev si effettua fino a 4,5 ore dall’esordio, in base allo studio ECASS 3 (Xxxxx W et al, 2008), recepito dalla ESO ed EMA, con il parere favorevole del Comitato Etico di Modena, anche se la nuova finestra temporale è in corso di valutazione da parte dell’AIFA.

Criteri Inclusione

• Pazienti di ambo i sessi di età compresa fra i 18-80 aa

• Ictus ischemico responsabile di un deficit misurabile di linguaggio, motorio, cognitivo, di sguardo, del visus e/o di neglect. L’ictus ischemico è definito come un evento caratterizzato da un deficit neurologico focale ad esordio improvviso, presumibilmente causato da ischemia cerebrale dopo esclusione CT di una emorragia cerebrale

• Inizio dei sintomi entro 4.5 ore (alla somministrazione di t-PA)

• Sintomi presenti per almeno 30 minuti e non significativamente migliorati prima del trattamento (nota1). I sintomi vanno distinti da quelli di un episodio di ischemia generalizzata (cioè una sincope), di una crisi epilettica o di una crisi di emicrania.

• I pazienti (o un familiare) debbono aver espresso la loro volontà ad essere trattati e aver dato il consenso all’utilizzo dei loro dati e alle procedure di follow-up

Criteri di Esclusione Controindicazioni assolute

• Emorragia intracranica alla TAC cerebrale

• Sospetto clinico di ESA, anche se TAC normale

• Somministrazione di eparina endovena nelle precedenti 48 ore e aPTT eccedente limite normale superiore del laboratorio

• Conta piastrinica < 100.000/mm3

• Diatesi emorragica nota

• Sanguinamento grave in atto o recente

• Storia o sospetto di emorragia intracranica in atto

Controindicazioni relative:

• Ictus grave clinicamente (es. NIHSS >25) e/o sulla base di adeguate tecniche di neuroimmagini

• Insorgenza dell’ictus > 4.5 ore o ora di insorgenza non nota o al risveglio

• Deficit lieve o rapido miglioramento dei sintomi (30 minuti) (NOTA 1)

• Crisi convulsiva all’esordio dell’ictus (VEDI SOTTO)

• Paziente con storia di ictus e diabete concomitante (VEDI SOTTO)

• Ictus negli ultimi 3 mesi

• Ipertensione arteriosa grave non controllata:

PAS > 185 mmHg, o PAD > 110 mmHg, o terapia aggressiva* necessaria per riportare la PA entro questi limiti (*secondo linee guida: urapidil o trandate ev) . Secondo le linee guida italiane SPREAD 2010, la terapia trombo litica ev può essere somministrata una volta raggiunto e mantenuto il range pressorio PAS< 185 e PAD <110. Tale range dovrà essere mantenuto anche nelle successive 24 ore dopo la terapia trombo litica.

• Glicemia < 50 o > 400 mg/dl

• Endocardite batterica

• Paziente in terapia antiacoaulante orale (TAO).

• Intervento chirurgico maggiore o grave trauma (< 3 mesi)

• Recenti (< 10 giorni) massaggio cardiaco esterno, trauma, parto, puntura di vaso sanguigno non comprimibile (es. vena succlavia o giugulare)

• Malattia ulcerosa del tratto gastroenterico (<3mesi)

• Storia di patologie del SNC (neoplasia, aneurisma, intervento chirurgico cerebrale o midollare)

• Aneurisma arterioso, malformazione artero-venosa, neoplasia con aumentato rischio emorragica

• Pancreatite acuta

• Grave epatopatia, compresa insufficienza epatica, cirrosi, ipertensione portale (varici esofagee), epatite attiva

• Retinopatia emorragica, es in diabetici alterazioni del visus

• Alto rischio emorragico per comorbidità

NOTE

Nota 1. Non vi è un limite inferiore al punteggio NIHSS, in particolare quando il deficit riguarda il linguaggio e il circolo posteriore per il quale è nota la minore sensibilità del punteggio NIHSS. Particolare attenzione prima di escludere un paziente dal trattamento trombolitico in caso di disturbi di tipo afasico o motorio in rapido miglioramento specie con NIHSS di partenza elevati. E’ documentato infatti che pazienti con NIHSS>10 mostrano generalmente una occlusione di un principale vaso intracranico. Il rapido miglioramento potrebbe essere correlato all’attivazione di temporanei compensi emodinamici, senza ricanalizzazione del vaso occluso.

In caso di punteggio molto basso (NIHSS<4) ma con documentazione di un vaso maggiore chiuso alla CTA o RMNA, congruo con i sintomi, la trombolisi è da considerare.

E’ dimostrato da un recente studio che il 25% dei pazienti esclusi dal trattamento trombolitico perché lievi (“too good to treat”), hanno presentato successivamente un peggioramento clinico con conseguente esitp sfavorevole (Xxxxx E et Al. Poor outcomes in patients who do not receive intravenous tPA because of mild or improving ischemic stroke. Stroke 2005;36:2497-99)

Nota 2. Studio SYNTHESIS EXPANSION: in caso di presenza del Neuroradiologo interventista, della disponibilità della sala angiografica e di presenza del Neurologo della Stroke Unit il paziente che soddisfa i criteri per la trombolisi ev standard può essere randomizzato nel trial Synthesis Expansion che confronta la trombolisi ev con la trombolisi IA entro 4.5 ore dall’esordio dei sintomi (vedi sezione trial clinici). E’ pertanto necessario avvisare il Neurologo della Stroke Unit (se presente) già al momento dell’arrivo in PS del paziente con codice trombolisi.

SCENARIO 2

TRATTAMENTO IN CASO DICONTROINDICAZIONI A TROMBOLISI EV

1. GRAVITA’ CLINICA

Ictus grave clinicamente (es. NIHSS >25), in particolare per coinvolgimento del circolo posteriore (occlusione dell’arteria basilare) o se intubato o sedato prima della valutazione neurologica (NIHSS non valutabile).

Prima di escludere il paziente dal trattamento perché troppo grave o non valutabile eseguire in urgenza all’arrivo in PS, contestualmente alla TC encefalo basale, negativa per emorragia, anche: Angio TC TSA e TC perfusion (in alternativa RMN encefalo con sequenze DWI-PWI, MRA-TOF intracranica).

1° scelta

Trombolisi INTRA-ARTERIOSA (IA) con i seguenti criteri di inclusione:

• Ampio mismatch (>50%) presente a CT perfusion (o MRI DWI-PWI) con occlusione di arteria intra e/o extracranica

• Risultano soddisfatti i rimanenti criteri di inclusione ed esclusione (solo assoluti) per trombolisi ev

• disponibile la sala angiografica

• disponibile il Neuroradiologo interventista

2° scelta

Trombolisi ENDOVENOSA (EV) con i seguenti criteri di inclusione:

• Non disponibile la sala angiografica e/o il Neuroradiologo interventista

• Ampio mismatch presente (>50%) a CT perfusion (o MRI DWI-PWI) con occlusione di arteria intra e/o extracranica, in particolare da considerare in pazienti con ictus da occlusione del circolo vertebro-basilare

• Risultano soddisfatti tutti i rimanenti criteri di inclusione ed esclusione (assoluti e relativi) per trombolisi ev

In caso di mancato miglioramento (calcolato entro fine infusione del tPA con miglioramento di 4 punti alla scala NIHSS o valore di NIHSS che persiste > 10) dopo terapia trombolitica endovenosa, persistenza di occlusione vasale (valutata con metodica neurosonologica se presente neurosonologo), previa TC encefalo di controllo ed eventuale controllo di TC perfusione e angioTAC (da concordare con il Neuroradiologo interventista) e qualora sia disponibile il Neuroradiologo Interventista è possibile procedere a trombolisi RESCUE (vedi di seguito).

2. CRISI CONVULSIVA ALL’ESORDIO DELL’ICTUS

La crisi epilettica all’esordio non è una controindicazione assoluta al trattamento trombolitico, ma occorre dimostrare con tecniche di neuroimmagini la diagnosi certa di ictus.

Prima di escludere il paziente dal trattamento pertanto è indicato eseguire in urgenza all’arrivo in PS, contestualmente alla TC encefalo basale, negativa per emorragia, anche:

Angio TC TSA e TC perfusion (in alternativa RMN encefalo con sequenze DWI-PWI, MRA-TOF intracranica). In caso di conferma di ictus (occlusione vaso intracranico, ipoperfusione alla CT perfusion) si può procedere con trattamento trombolitico ev standard entro 4.5 ore dall’esordio.

3. PAZIENTE CON STORIA DI ICTUS E DIABETE CONCOMITANTE

Nel caso di questi pazienti non vi è una controindicazione in base ai dati del registro SITS-ISTR, che mostrano simile beneficio della terapia trombolitica rispetto ai pazienti non diabetici. Un recente studio su 29.500 pazienti ha confrontato l’esito dei pazienti diabetici (19%), con pregresso ictus (17%) ed entrambe le condizioni (6%) tra i pazienti sottoposti a trombolisi del registro SITS- ISTR con quello di pazienti di controllo, non trattati con trombolisi provenienti dal registro VISTA (Virtual International Stroke Trials Archive). Anche in questa categoria di pazienti la trombolisi endovenosa determina outocomes migliori (Xxxxxx NK et al., Neurology 2011; 77:1866).

La raccomandazione della Consensus Conference del Karolinska (allegato 1): indica la possibilità di trattamento con trombolisi endovena off-label in questi pazienti (Classe III, livello di evidenza C).

4. GLICEMIA < 50 O > 400 MG/DL

Valori di glicemia <50 mg/dl necessitano l’immediata correzione per escludere stroke-mimic da ipoglicemia con segni neurologi focali. Qualora il disturbo neurologico permanga occorre dimostrare con tecniche di Neuroimmagini la diagnosi certa di ictus.

Prima di escludere il paziente dal trattamento pertanto è indicato eseguire in urgenza - all’arrivo in PS - contestualmente alla TC encefalo basale, negativa per emorragia, anche:

In caso di valori di glicemia >400 mg/dl prima di escludere il paziente dal trattamento si può abbassare la glicemia con insulina rapida e eventualmente pompa insulinica ev. In caso di controllo dei valori glicemici sotto i 400 mg/dl si può procedere con trattamento trombolitico ev standard entro 4.5 ore dall’esordio.

5. ENDOCARDITE BATTERICA

L’endocardite batterica è una controindicazione relativa alla trombolisi endovenosa, per il rischio di disgregazione del trombo ed embolizzazione settica. Pochi sono i dati di letteratura, relativi a casi clinici di trattamenti trombolitici per ictus e IMA. Oltre ai rischi emorragici e di embolizzazione settica ciò che pone più limiti al trattamento è la mancanza di un meccanismo fisiopatologico che porti a documentare come il tPA possa avere un effetto trombolitico su un embolo settico. Si consiglia pertanto nel paziente con ictus ischemico acuto con nota/sospetta endocardite batterica

dopo valutazione clinica, studio neuro radiologico (TC perfusion, angioTAC TSA e intracranica) di considerare come prima scelta terapeutica la trombolisi intra-arteriosa (trombectomia).

• Di Salvo TG, Xxxxxx SB, O’Gara PT, Xxxxxxx GP, DeSanctis RW. Fatal intracerebral hemorrhage following thrompolytic therapy of embolic myocardial infarction in unsuspected infective endocarditis. Clin Cardiol 1994;17(6):340-4

• Xxxxxx XX, Xxxxxx DE. Thrombolytics in infectious endocarditis associated myocardial infarction. J Emerg Med. 2001;21(4):401–6.

• Xxxxx M, Xxx CC, Xxxxxxxx RE, Xxxxxxxxxx AA. Successful intravenous thrombolysis in ischemic stroke caused by infective endocarditis. Neurocrit Care. 2007;6(2):117-20.

• Xxxxxxxxxxxxxxx X., Xxxxxxxxx M., Xxxxxx F., Xxxxxxxx P., Xxxxxx N., Xxxx A. Thrombolytic treatment in two patients with concealed endocarditis (abstract XL congresso SIN 2009). Neurol Sci 2009;30:S146-7.

• Xxxxx P, Xxx SH, Xxxxxx xxxxxxxx X, Xxxxx GA.Intracranial Hemorrhage Following Thrombolytic Use for Stroke Caused by Infective Endocarditis. Neurocrit Care 2009 Aug 18.

6. INTERVENTO CHIRURGICO MAGGIORE O GRAVE TRAUMA RECENTE

In caso di pazienti con ictus ischemico acuto e recente intervento chirurgico maggiore o trauma maggiore (<14 giorni secondo lo studio NINDS e le linee guida AHA, <3 mesi per EMEA), dopo valutazione clinica, valutazione del rischio emorragico e neuroradiologica approfondita (TC perfusion, angioTAC TSA e intracranica) è da considerarsi la possibilità di trombolisi intra- arteriosa, secondo le linee guida americane (Xxxxxx P et al, NeuroIntervent Surg 2010 NeuroIntervent Surg 2010), recepite anche dalle linee guida italiane SPREAD 2010. In caso non sia possibile trattare il paziente con trombolisi intrarteriosa non va comunque esclusa a priori la possibilità di trattare con trombolisi endovenosa alla luce anche dei dati di letteratura sui trattamenti off-label.

• Meretoja A, Xxxxxxx J, Xxxxxxxxxx T, Xxxxx S, Xxxxx V, Xxxxxx S, Häppölä O, Xxxxxxxxx PJ, Xxxxxxxxx S, Xxxxxxxx K, Xxxxxxxxxx J, Xxxxxxxx K, Xxxxxxxx T, Xxxxxxx O, Silvennoinen H, Xxxxxx L, Xxxxxxx D, Xxxxxxx M, Kaste M. Off-label thrombolysis is not associated with poor outcome in patients with stroke. Stroke. 2010 Jul;41(7):1450-8.

• Xxxxxx L, Xxxxxxxx C, Xxxxxxx HB, Kiphuth IC, Xxxxxx S, Xxxxxxxx M. Off-label thrombolysis for acute ischemic stroke: rate, clinical outcome and safety are influenced by the definition of 'minor stroke'. Cerebrovasc Dis. 2011;32(2):177-85.

• the SITS-EAST Collaborative Group. Intravenous alteplase in ischemic stroke patients not fully adhering to the current drug license in Central and Eastern Europe. Int J Stroke. 2012 Feb 7.

• Xxxxxxx M, Xxxxxx-Xxxxxxx A, Xxxxxx-Xxxxxxxxx J, Xxxxxxx-Xxxxxxxx V, Xxxxxxxxx- Xxxxxxx I, Xxxxxxxx-Xxxxxxxx A, Xxxxxx MC, Xxxxxx-Xxxxx MA, Xxxxxx xx Xxxxxxxx M, Xxxxxxx X. Off-label intravenous thrombolysis in acute stroke. Eur J Neurol. 2012 Mar;19(3):390-4.

7. TERAPIA ANTICOAGULANTE ORALE

PAZIENTI IN TAO INR<1,7.

Secondo le linee guida americane i pazienti in TAO con INR <1,7 possono essere sottoposti a trombolisi endovenosa (1). Un recente studio ha inoltre valutato il rischio emorragico in pazienti trattati con trombolisi endovenosa e INR<2, tale rischio non è risultato aumentato (2).

PAZIENTI IN TAO INR>1,7.

In questi pazienti è indicata solo la terapia trombolitica intra-arteriosa (3), previa disponibilità del neuroradiologo interventista, studio neuroradiologico (TC encefalo perfusione angioTAC extra- intracranica o studio RMN encefalo con sequenze DWI-PWI, MRA-TOF intracranica), informazione del paziente e dei famigliari dei rischi e benefici della procedura.

Bibliografia

1. Xxxxxx G et al. Antithrombotic and Thrombolytic Therapy for Ischemic Stroke*American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008: 133 : 6 June, supplement.

2. Xxxxxx MC et al Safety and Outcomes following Thrombolytic Treatment in Stroke Patients Who Had Received Prior Treatment with Anticoagulants. Cerebrovasc Dis 2012; 33: 231- 239.

3. Xxxxxx P et al. Indications for the performance of intracranial endovascular neurointerventional procedures. A scientific statement from the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Interdisciplinary Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. J NeuroIntervent Surg 2010;2:177e188. doi:10.1161/circulationaha.109.192217

8. GRAVIDANZA

L’ictus in gravidanza pone una serie di quesiti legati a:

• Conseguenze potenzialmente devastanti per la madre e per il prodotto del concepimento

• Problemi nella terapia (trombolisi, antitrombotici)

• Incidenza 34/100.000 parti (popolazione ospedaliera), in studio di popolazione ictus ischemico 11/100.000, Emorragie 9/100.000 (incluso il post partum).

• 2% hanno trombosi dei seni venosi cerebrali

• Rischi: età >35, razza nera, ipertensione, fumo, cardiopatia, diabete , LES, falcemia, emicrania, droghe e alcool, parto cesareo, trombofilia, gravidanze multiple, parità elevata, infezioni ed eclampsia.

Trombolisi e gravidanza

Diversi sono i casi riportati in letteratura di pazienti in gravidanza trattati con trombolisi.

I dati di una revisione (1) del 2006 su 28 casi di donne gravide di cui 10 con ictus possono essere così riassunti:

• I casi di ictus trattati con rt-PA sono solo 3 (2 e.v., 1 i.a.), di cui 2 con esito buono, una rimasta emiplegica. I bambini erano normali

• Un caso di trombosi dei seni venosi trattato con successo, bambino normale

• rt-PA non teratogeno

• 5/25 casi di morte fetale dopo trombolisi per altre cause (EP, IMA), 3 per aborto terapeutico.

• Non rischi maggiori per la madre

In letteratura sono riportati in totale dati su 30 pazienti con ictus in gravidanza trattate con trombolisi, le principali conseguenze possono essere un parto prematuro, la morte del feto, oltre al rischio emorragico insito nella procedura. L’alteplase non attraversa però la placenta, e i dati disponibili indicano che non è teratogeno, i bambini nati da donne trattate non hanno riportato danni. Quello che pertanto in base ai dati disponibili si può suggerire è che il trattamento in gravidanza è fattibile, valutando che 42-63% delle donne con stroke in gravidanza hanno deficit residui.”(2).

Bibliografia:

1. Xxxxx Xxxxxxxxx et al, Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 21(3), 271–276, 2006.

2. De Xxxxxx et al. Intravenous Alteplase for Stroke Beyond the Guidelines and in Particular Clinical Situations. Stroke. 2007;38:2612-2618.

Anticoagulanti gravidanza (LG AHA)

Warfarin embriotossico tra la 6 e la e 12 settimana di gestazione

Da evitare nelle ultime settimane per evitare sanguinamenti da trauma al feto Aspirina <150 mg sicura dopo il 1 trimestre

• In caso di ictus e alto rischio tromboembolico (valvulopatia, coagulopatia): Eparina a basso peso molecolare (LMWH o eparina non frazionata (UFH) da sospendere 24 ore prima di induzione di parto; oppure passare a Warfarin dopo la 13 settimana fino a metà 3° trimestre (Classe IIb, Livello di evidenza C)

• In caso di ictus e basso rischio tromboembolico : LMWH o UFH nel primo trimestre, poi aspirina a basse dosi fino alla fine della gravidanza

Trombolisi e mestruazione

Il trattamento è controindicato in caso di potenziali fonte di sanguinamento .

• 9 pazienti trattate nel trial NINDS (5 rt-PA e 4 placebo) + 25 in letteratura (streptokinasi- urokinasi e rt-PA). Su 29 trattate, 2 hanno richiesto trasfusione.

Usare con cautela, avvertire la paziente e predisporre per trasfusione.

SCENARIO 3

TROMBOLISI IN PAZIENTI CON ICTUS NON DATABILE O RISVEGLIO

Prima di escludere il paziente dal trattamento eseguire in urgenza all’arrivo in PS, contestualmente alla TC encefalo basale, negativa per emorragia, anche :

Angio TC TSA e TC perfusion

(in alternativa RMN encefalo con sequenze DWI-PWI, MRA-TOF intracranica)

1° scelta

Criteri di inclusione per trombolisi IA

• Mismatch presente a CT perfusion (o MRI DWI-PWI)

• Risultano soddisfatti i rimanenti criteri di inclusione ed esclusione (solo assoluti) per trombolisi ev

• disponibile la sala angiografica

• disponibile il Neuroradiologo interventista

• Informazione del paziente e dei famigliari sui rischi e benefici della terapia off-label

• Invio in sala angiografica per trombolisi intrarteriosa, previo contatto Neurorianimatore la cui presenza in sala angiografica è fondamentale. In sala angiografica sarà inoltre presente il Neurologo che ha seguito il paziente. Il paziente continuerà il monitoraggio e la registrazione dei parametri vitali durante la procedura e ogni tipo di trattamento (farmacologico e/o trombolisi meccanica) verrà annotata in cartella.

2° scelta

Criteri di inclusione per trombolisi ev

• Ampio mismatch presente nella CT perfusion (o MRI DWI-PWI)

• Risultano soddisfatti tutti i rimanenti criteri di inclusione ed esclusione (assoluti e relativi) per trombolisi ev

• Non disponibile la sala angiografica e/o il Neuroradiologo interventista

• Informazione del paziente e dei famigliari sui rischi e benefici della terapia off-label

SCENARIO 4

TRATTAMENTO TROMBOLITICO IN PAZIENTI DI ETA’ SUPERIORE 80 ANNI

1. Arruolamento del paziente all’interno degli studi in corso:

STUDIO TESPI

I pazienti con ictus ischemico e >80 anni possono essere inclusi nello studio RCT TESPI se soddisfatti i seguenti criteri:

• disponibilità del Neurologo della Stroke Unit per randomizzare il paziente

• possibilità di eseguire il trattamento entro 3 ore dall’esordio dei sintomi

• NIHSS<17

• Glicemia basale <200 mg/dl

• Soddisfatti i rimanenti criteri per trombolisi ev standard

• Autonomia pre-ictus (mRS 0-1)

STUDIO DIAS 4

I pazienti con ictus ischemico ed età compresa fra 80-85 anni possono essere inclusi nello studio RCT DIAS 4 (desmoteplase ev versus placebo) se soddisfatti i seguenti criteri:

• disponibilità del Neurologo della Stroke Unit per randomizzare il paziente

• riscontro di arteria intracranica occlusa: MCA, ACA, PCA a una delle seguenti indagini: AngioTC TSA o AngioRM TSA eseguita prima della randomizzazione

• pervietà dei vasi extracranici carotidei a AngioTC TSA o AngioRM

• mismatch presente a TC perfusione o RMN DWI-PWI o comunque infarto <1/3 MCA o ½ ACA o PCA.

• Esclusione di ictus vertebro-basilari

• possibilità di eseguire il trattamento entro 9 ore dall’esordio dei sintomi

• NIHSS 4-24

• Se TAO con INR <1.6

• Glicemia <200 mg/dl

• Soddisfatti i rimanenti criteri per trombolisi ev standard

• Autonomia pre-ictus (mRS 0-1)

2. TROMBOLISI off-label

In caso di assenza del neurologo della Stroke Unit o se non soddisfatti i criteri di arruolamento per lo studio TESPI o DIAS4 il paziente con ictus ischemico, di età compresa tra gli 80-90 anni ed in ottime condizioni può essere indirizzato al trattamento trombolitico alla luce delle evidenze di letteratura (registro SITS) e della Consensus Conference del Karolisnka (allegato 1).

In caso di ictus con NIHSS>14 o comunque clinicamente classificabili come TACI alla classificazione OCSP di Xxxxxxx è indicato eseguire in urgenza all’arrivo in PS, contestualmente alla TC encefalo basale, negativa per emorragia, anche :

Angio TC TSA e TC perfusion (in alternativa RMN encefalo con sequenze DWI-PWI, MRA-TOF intracranica) al fine di stratificare il rischio/beneficio del trattamento nell’ultraottantenne.

Informazione del paziente e dei famigliari sui rischi e benefici della terapia off-label.

1° scelta

Criteri di inclusione per trombolisi ev *

• mRS 0-1 pre ictus (si raccomanda al momento della raccolta anamnestica dai familiari un’attenta valutazione delle performance motorie e cognitive tali da garantire un reale grado di autonomia pre-ictus)

• Mismatch presente a CT perfusion (o MRI DWI-PWI)

• Risultano soddisfatti tutti i rimanenti criteri di inclusione ed esclusione (assoluti e relativi) per trombolisi ev

• Non disponibile la sala angiografica e/o il Neuroradiologo interventista

2° scelta

Criteri di inclusione per trombolisi IA

• Mismatch presente a CT perfusion (o MRI DWI-PWI)

• Valutazione alla AngioTC TSA di accesso anatomico possibile (alla luce delle frequenti tortuosità dei vasi dell’anziano).

• Risultano soddisfatti i rimanenti criteri di inclusione ed esclusione (solo assoluti) per trombolisi ev

• disponibile la sala angiografica

• disponibile il Neuroradiologo interventista

SCENARIO 5

TRATTAMENTO RESCUE

(trombolisi ev a dose piena seguita da trombolisi IA)

Criteri di inclusione:

• paziente sottoposto a trombolisi ev

• non miglioramento dopo trombolisi ev (miglioramento <4 punti NIHSS entro la fine dell’infusione di tPA, e comunque NIHSS>10)

• riscontro di arteria intracranica occlusa (± extracranica: carotide interna o vertebrale): MCA, ACA, PCA, basilare, vertebrale a una delle seguenti indagini: EcoDoppler, AngioTC o AngioRM eseguita prima o dopo trombolisi endovenosa

• mismatch presente alla CT perfusion (o MRI DWI-PWI) prima o dopo trombolisi endovenosa

• presenza di Neuroradiologo interventista

• disponibilità della sala angiografica

Invio in sala angiografica per trombolisi intrarteriosa, previo contatto Neurorianimatore la cui presenza in sala angiografica è fondamentale. In sala angiografica sarà inoltre presente il Neurologo che ha seguito il paziente. Il paziente continuerà il monitoraggio e la registrazione dei parametri vitali durante la procedura e ogni tipo di trattamento (farmacologico e/o trombo lisi meccanica) verrà annotata in cartella. A fine procedura il paziente verrà sottoposto a Tc encefalo di controllo per escludere sanguinamenti.

Al termine della procedura in base all’andamento della stessa si deciderà se riportare il paziente in Stroke Unit o se trasferire il paziente in Neurorianimazione, con i medesimi criteri riportati nella procedura a seguito (allegato 2), per il trattamento intra-arterioso eseguito in urgenza.

STUDI CLINICI IN CORSO

STUDIO SYNTHESIS EXPANSION

Confronto tra trombo lisi ev e ia entro 4,5 ore dall’esordio. L’arruolamento dovrebbe terminare in aprile 2012, sono stati reclutati presso il Centro di Modena 50 pazienti in 3 anni. I criteri di inclusione ed esclusione sono gli stessi della trombolisi endovenosa (Vedi sopra), oltre alla disponibilità del Neuroradiologo interventista e la presenza del Neurologo della Stroke Unit per la randomizzazione.

STUDIO TESPI pazienti con ictus ischemico e >80 anni possono essere inclusi nello studio RCT TESPI se soddisfatti i seguenti criteri:

• disponibilità del Neurologo della Stroke Unit per randomizzare il paziente

• possibilità di eseguire il trattamento entro 3 ore dall’esordio dei sintomi

• NIHSS<17

• Glicemia basale <200 mg/dl

• Soddisfatti i rimanenti criteri per trombolisi ev standard

• Autonomia pre-ictus (mRS 0-1)

Studio DIAS4

I pazienti con ictus ischemico ed età compresa fra 18-85 anni possono essere inclusi nello studio RCT DIAS 4 (desmoteplase ev versus placebo) se soddisfatti i seguenti criteri:

• disponibilità del Neurologo della Stroke Unit per randomizzare il paziente

• riscontro di arteria intracranica occlusa: MCA, ACA, PCA a una delle seguenti indagini: AngioTC TSA o AngioRM TSA eseguita prima della randomizzazione

• pervietà dei vasi extracranici carotidei a AngioTC TSA o AngioRM

• mismatch presente a TC perfusione o RMN DWI-PWI o comunque infarto <1/3 MCA o ½ ACA o PCA.

• Esclusione di ictus vertebro-basilari

• possibilità di eseguire il trattamento entro 3-9 ore dall’esordio dei sintomi

• NIHSS 4-24

• Se TAO con INR <1.6

• Glicemia <200 mg/dl

• Test di gravidanza negativo

• Soddisfatti i rimanenti criteri per trombolisi ev standard

• Autonomia pre-ictus (mRS 0-1)

ALLEGATI

Allegato 1 KAROLINSKA STROKE UPDATE 2010

Allegato 2 Procedura Applicativa Allegato 3 Valutazione degli esiti Allegato 4 gestione delle complicanze

KAROLINSKA STROKE UPDATE 2010

Reperfusion Therapy - Thrombectomy

The Consensus Statement includes two parts, the Consensus Statement itself, and the Recommendation to the European Stroke Organisation (ESO) on revision of ESO Guidelines. Please note that the final text of the Guidelines, is decided by ESO and that the recommendation in this document may not be the final guidelines version. As soon as the guidelines are confirmed, they will appear on this website as well as on the ESO website xxx.xxx-xxxxxx.xxx

I. Karolinska Stroke Update Consensus Statement Reperfusion Therapy - Thrombectomy

The following Consensus Statement was adopted by the 8th Karolinska Stroke Update meeting on November 15, 2010.

The consensus statement was proposed by the chairman of the session, Professor Xxxxx Xxxxxxx, Heidelberg, and the session secretary Dr Xxxxxx Xxxxxx, Stockholm, together with the speaker of the session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speaker in this session were Professor Xxxxx Xxxxxxxxxxx, Minden.

CONTROVERSY TO DISCUSS AT THE 2010 CONSENSUS SESSION:

Is thrombectomy evidence based treatment in acute ischaemic stroke?

A. Background - previous statements

Karolinska 2004:

Various mechanical means of clot removal and angioplasty are under investigation. The safety and efficacy of these endovascular techniques including stent protected angioplasty in acute stroke need further assessment.

Karolinska 2006

Large vessel stroke is highly morbid if left untreated

Mechanical embolectomy with the MERCI device opens vessels 54% of the time, a rate superior to natural history

Adjuvant IA thrombolysis improves final recanalisation up to 69% Clinical outcome is significantly better if the vessel is recanalised Mortality is significantly lower if the vessel is recanalised

Target vessel recanalisation is an independent predictor of good clinical outcome and mortality using multivariate modelling

Clinically significant procedure complications occur in 4.5-7.1% of cases

It is safe to treat patients with thrombectomy who have failed IV t-PA (defined as the vessel remaining closed after IV t-PA infusion)

The treatment is cleared by FDA for in acute large vessel stroke and may also be used for failed i.v. thrombolysis (Grade C)

Randomised data is necessary before one can conclude that mechanical recanalisation mitigates stroke.

ESO 2008

The MERCI (Mechanical Embolus Removal in Cerebral Embolism) trial evaluated a device that removed the thrombus from an intracranial artery. Recanalization was achieved in 48% (68/141) of patients in whom the device was deployed within 8 h of the onset of stroke symptoms. No RCTs with outcome data are available for any recanalization devices.

AHA 2009 2

Although the Concentric Merci device can be useful for extraction of intra-arterial thrombi in appropriately selected patients, the utility of the device in improving outcomes after stroke remains unclear (Class IIb, Level of Evidence B).

The usefulness of other endovascular devices is not yet established, but they may be beneficial. (Class IIb, Level of Evidence C)

NEW EVIDENCE

The topic mechanical thrombectomy in acute ischemic stroke patients has been discussed at the Karolinska Meeting in 2006. Since that time several devices have been evaluated for treatment of acute ischemic stroke patients and several case series with these devices have been published. Some examples of those devices are improved models of the MERCI-retriever (3), the EKOS ultrasound device (4), the PENUMBRA system (5), and the PHENOX CRC-retriever (6). A rather new approach is the use of temporary stent systems such as the SOLITAIRE stent (7-8).

Most of these devices have been evaluated in patients not suitable (e.g. because of extended time window) or with contraindications (e.g. oral anticoagulation) for intravenous thrombolysis with rtPA9. The uniform messages of these case series are, that the recanalization rate was higher than reported compared to natural history and iv rt-PA in historical controls, that outcome was better in patients with early vessel recanalization as opposed to persistent occlusion, and that mortality was increased if recanalization could not be achieved (10). However, selected patient cohorts with usually severe strokes were included in those studies. Thus, it is hard to compare these results with data from controlled trials or registries with intravenous thrombolytic treatment. Only limited data are available for comparison of different devices (11) and no randomized trials compared to medical treatment have been completed so far. Furthermore there appears to be a correlation of outcome and onset to treatment times in indirect comparison of the different studies, and it is unclear if recanalization also results in an improved reperfusion.

There is one randomized clinical trial (IMS III) ongoing in the US comparing iv-thrombolysis with different intraarterial approaches (12). It is reasonable that European centers will be able to join this study in the nearer future. Given the lack of head to head comparisons to date, it is not possible to determine whether one endovascular treatment approach is better than another or better than medical therapy alone. However, mechanical thrombectomy will without doubt play a continuing role in acute stroke treatment. Interventionalists need to be trained in these procedures. As patients need to be transferred to tertiary centers, where trained interventionalists are available, algorithms for those transfers have to be established (13).

Another topic under discussion is whether intraarterial treatment needs to be done with general anesthesia or if it can be done in conscious sedation (14). There have been some retrospective studies and registries indicating that local anesthesia is feasible and carries no increased risk while offering some advantages (15-16). A recent controversy concluded that future prospective randomized controlled trials of endovascular treatment should evaluate the impact of sedation modality on safety of the intervention, technical success, time to recanalization, and clinical outcome (14).

PROPOSAL FOR A NEW CONSENSUS STATEMENT, MODIFIED AFTER DISCUSSION WITH PARTICIPANS AT THE KSU MEETING 2010.

Large artery occlusion is associated with a high morbidity and mortality if left untreated Mechanical thrombectomy achieves higher recanalization rates compared to historical controls with or without intravenous rt-PA

The odds for favorable outcome in general are significantly increased with early vessel recanalization

Due to the lack of evidence of randomized control trials for clinical efficacy, mechanical thrombectomy should not be used in clinical routine

However, in selected patients (e.g. with indication for iv-treatment but also contraindication), endovascular approaches may be considered as part of a institutional protocol

If treatment is done outside a RCT, data should be included in a multicenter registry including assessment of three months outcome

Future prospective randomized controlled trials of endovascular treatment should also evaluate the impact of sedation modality on safety of the intervention, technical success, time to recanalization, and clinical outcome

REFERENCES

1. ESO Writing Committee. Guidelines for Management of Ischaemic Stroke and Transient Ischaemic Attack 2008. Cerebrovasc Dis. 2008;25:457-507

2. Xxxxxx PM, Xxxxxxxxxx HC, Xxxxxxxxx RT, Barnwell SL, Xxxxxxx MA, Xxxxx R, XxXxxxxxx CG, Xxxxxx DK, Xxxxx D, Xxxxxxxx XX. Indications for the performance of intracranial endovascular neurointerventional procedures: a scientific statement from the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Interdisciplinary Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation. 2009;119:2235-2249

3. Xxxxx WS, Xxxx G, Xxxxx J, Xxxxxx R, Xxxxxxxxx G, Xxxxxxxxxx DS, Xxxxxx HL, Xxxxx MM, Xxxxxxxxx RT, Xxxxxxxx S, Xxxxx YP, Xxxx D, Xxxxxxxx T, Xxxxxxxxx F, Xxxxxx D, Xxxxxxx C, Xxxxxxxxx W, Xxxxx M, Xxxxxx G, Xxxxxxxxx IE. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008;39:1205-1212

4. Xxxxx BR, Xxxxxx GM, Barnwell SL, Xxxxx W, Xxxxxxx TR, Xxxxx A, Xxxx PA, Qureshi AI. North American clinical experience with the EKOS MicroLysUS infusion catheter for the treatment of embolic stroke. AJNR Am J Neuroradiol. 2003;24:534-538

5. Bose A, Xxxxxx H, Xxxxx X, Xxxxx W, Xxxxx TE, Xxxxxx X, Xxxxxx V, Sit SP. The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol. 2008;29:1409-1413

6. Mordasini P, Xxxxxx M, Xxxxxxxxxx C, Xxxxxxx G, Xxxxxxx U, Xxxxxxxx J, Xxxxxx M, Xxxxxx

J. In vivo evaluation of the Phenox CRC mechanical thrombectomy device in a swine model of acute vessel occlusion. AJNR Am J Neuroradiol. 2010;31:972-978

7. Xxxx C, Xxxxxxxxxxxx P, Xxxxxx S, Xxxxxx X, Xxxxx A, Xxxxxx C, Xxxxxxxxxx K, Xxxxxx M, Xxxxxx H, Xxxxxx MS, Xxxxx W. Stent-Assisted Mechanical Recanalization for Treatment of Acute Intracerebral Artery Occlusions. Stroke. 2010

8. Xxxxxxx C, Xxxxxx L, Xxxxxxxx C, Xxxxxx M, Xxxxx M, Xxxxx de la Ossa N, Xxxxxxxxxxx M, Xxxxxx MR, Xxxxxxxx S, Xxxxxxx A. Mechanical thrombectomy with the Solitaire AB device in large artery occlusions of the anterior circulation: a pilot study. Stroke. 2010;41:1836-1840

9. Stead LG, Xxxxxxx RM, Xxxxxxxx MF, Xxxxxxxxxx AA, Xxxxxx WW. Percutaneous clot removal devices in acute ischemic stroke: a systematic review and meta-analysis. Arch Neurol. 2008;65:1024-1030

10. Xxx JH, Xxxxx JL. The impact of recanalization on ischemic stroke outcome: a meta- analysis. Stroke. 2007;38:967-973

11. Xxxxxxxxxx C, Xxxxxxx G, El-Koussy M, Xxxxxxxxxx K, Reinert M, Xxxxxxxx J, Xxxxxx J. Mechanical thromboembolectomy for acute ischemic stroke: comparison of the catch thrombectomy device and the Merci Retriever in vivo. Stroke. 2008;39:1213-1219

12. Xxxxxx P, Xxxx MD, Xxxxxxx YY, Spilker J, Xxxxx EC, Xxxxxxxxxxx JA, Xxxxxxx AM, Xxxxxx R, Xxxxxxx P, Xxxxxx C, Xxxxxxxxx KJ, Xxxxx S, Xxxxxxx TA, Xxxxxxxxx JP. Methodology of the Interventional Management of Stroke III Trial. Int J Stroke. 2008;3:130-137

13. Xxxxxxxxxxx T, Xxxxxxxxxxxxxxx M, Xxxxxxx C, Xxxxxx A, Xxxxxxx HW, Xxxxxxx A, Xxxxx TE, Xxxxxxxxx H, Xxxxxxxx M, Fesl G. Drip, ship, and retrieve: cooperative recanalization therapy in acute basilar artery occlusion. Stroke. 2010;41:722-726

14. Xxxxxx CA, Xxxxx MH. General or Local Anesthesia During Endovascular Procedures. Sailing Quiet in the Darkness or Fast Under a Daylight Storm. Stroke. 2010

15. Abou-Chebl A, Xxx R, Xxxxxxx MS, Xxxxx TG, Xxxx EI, Xxxxxxxxxx DS, Xxx AJ, Xxx DP, Xxxxx MM, Xxxxx AH, Xxxxxx OO, Xxxxxxxxx SK, Xxxxxxxx RG, Xxxxx A, Xxxx M, Xxx Q, Xxxxx JS, Xxxxxx TN, Xxxx M, Xxxxx X. Xxxxxxxxx sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: preliminary results from a retrospective, multicenter study. Stroke. 2010;41:1175-1179

16. Xxxxx MA, Xxxxx F, Xxxx-Xxxx X, Xxxxxxxx T, Xxxxx AM, Xxxx A, Xxxxxx JI, Xxxxxxxxx B, Xxx R, Xxxxx V, Xxxxx SF, Xxxxxx MD, Xxxxxxxx LR, Xxxxxxxx M, Xxxxx TG. Comparison of safety and clinical and radiographic outcomes in endovascular acute stroke therapy for proximal middle cerebral artery occlusion with intubation and general anesthesia versus the nonintubated state. Stroke. 2010;41:1180-1184

RECOMMENDATION BY KAROLINSKA STROKE UPDATE PARTICIPANTS TO ESO GUIDELINES COMMITTEE TO REVISE ESO GUIDELINES

A. Current ESO guidelines:

ESO Guidelines 2008 regarding mechanical thrombectomy No recommendations

Intra-arterial recanalization devices

The MERCI (Mechanical Embolus Removal in Cerebral Embolism) trial evaluated a device that removed the thrombus from an intracranial artery. Recanalization was achieved in 48% (68/141) of patients in whom the device was deployed within 8 hours of the onset of stroke symptoms [1]. No RCTs with outcome data are available for any recanalization devices.

B. Suggested changes of the ESO guidelines as a result of the KSU 2010:

During the previous years several devices have been evaluated for treatment of acute ischemic stroke patients and some cohort studies with these devices have been published. Given examples of those devices are improved models of the MERCI-retriever[2], the EKOS ultrasound device[3], the PENUMBRA system[4], and the PHENOX CRC-retriever[5].

A novel approach is the use of temporary stent systems such as the SOLITAIRE stent[6, 7]. Most of these devices have been evaluated in patients not suitable or with contraindications for intravenous thrombolysis with rtPA[8].

The uniform messages of these series are, that the recanalization rate was higher than compared to natural history and iv rt-PA in historical controls, that outcome was better in patients with early vessel recanalization as opposed to persistent occlusion, and that mortality was increased if recanalization could not be achieved[9].

However, it is hard to compare these results with data from controlled trials or registries with intravenous thrombolytic treatment. No randomized trials with concurrent controls (placebo or IV thrombolysis with any drug) have been completed so far.

Given the lack of head to head comparisons to date, it is not possible to determine whether one endovascular treatment approach is better than another or better than medical therapy alone. There is one randomized clinical trial (IMS III) ongoing in the US comparing iv-thrombolysis with different intraarterial approaches[10]. Randomized controlled trials of endovascular treatment should evaluate the impact of sedation modality on safety of the intervention, technical success, time to recanalization, and clinical outcome [11].

B. Proposal for new guideline recommendations

Mechanical thrombectomy of large vessel occlusion achieves higher recanalization rates compared to historical controls with or without intravenous rt-PA. The odds for favorable outcome in general are significantly increased with early vessel recanalization.

Due to the lack of evidence of randomized control trials for clinical efficacy, mechanical thrombectomy should not be used in clinical routine

However, in selected patients (e.g. with indication for iv-treatment but also contraindication), endovascular approaches may be considered as part of a institutional protocol

If treatment is done outside a RCT, data should be included in a multicenter registry including assessment of three months outcome.

REFERENCES

1. Xxxxx WS, Xxxx G, Xxxxxxxx S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005;36:1432-8.

2. Xxxxx WS, Xxxx G, Xxxxx J, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 2008;39:1205-12.

3. Xxxxx BR, Xxxxxx GM, Barnwell SL, et al. North American clinical experience with the EKOS MicroLysUS infusion catheter for the treatment of embolic stroke. AJNR Am J Neuroradiol 2003;24:534-8.

4. Bose A, Xxxxxx H, Xxxxx K, et al. The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol 2008;29:1409-13.

5. Mordasini P, Xxxxxx M, Xxxxxxxxxx C, et al. In vivo evaluation of the Phenox CRC mechanical thrombectomy device in a swine model of acute vessel occlusion. AJNR Am J Neuroradiol 2010;31:972-8.

6. Xxxx C, Xxxxxxxxxxxx P, Xxxxxx S, et al. Stent-Assisted Mechanical Recanalization for Treatment of Acute Intracerebral Artery Occlusions. Stroke 2010.

7. Xxxxxxx C, Xxxxxx L, Xxxxxxxx C, et al. Mechanical thrombectomy with the Solitaire AB device in large artery occlusions of the anterior circulation: a pilot study. Stroke 2010;41:1836- 40.

8. Stead LG, Xxxxxxx RM, Xxxxxxxx MF, Xxxxxxxxxx AA, Xxxxxx WW. Percutaneous clot removal devices in acute ischemic stroke: a systematic review and meta-analysis. Arch Neurol 2008;65:1024-30.

9. Xxx JH, Xxxxx JL. The impact of recanalization on ischemic stroke outcome: a meta- analysis. Stroke 2007;38:967-73.

10. Xxxxxx P, Xxxx MD, Xxxxxxx YY, et al. Methodology of the Interventional Management of Stroke III Trial. Int J Stroke 2008;3:130-7.

11. Xxxxxx CA, Xxxxx MH. General or Local Anesthesia During Endovascular Procedures. Sailing Quiet in the Darkness or Fast Under a Daylight Storm. Stroke 2010.

REPERFUSION THERAPY - INTRAVENOUS THROMBOLYSIS

The Consensus Statement includes two parts, the Consensus Statement itself, and the Recommendation to the European Stroke Organisation (ESO) on revision of ESO Guidelines. Please note that the final text of the Guidelines is decided by ESO and that the recommendation in this document may not be the final guidelines version. As soon as the guidelines are confirmed, they will appear on this website as well as on the ESO website xxx.xxx-xxxxxx.xxx

I. Karolinska Stroke Update Consensus Statement

REPERFUSION THERAPY - INTRAVENOUS THROMBOLYSIS

The following Consensus Statement was adopted by the 8th Karolinska Stroke Update meeting on November 16th 2010.

The consensus statement was proposed by the chairman of the session, Professor Xxxxxx Xxxxx, Helsinki, Finland, and the session secretary Dr. Xxxxxxxx Xxxxxxxx, Stockholm, Sweden, together with the speakers of the session. The statement was then finally approved by the participants of the meeting after listening to the other presentations.

The speakers in this session were Professor Xxxxx X. Xxxxx, Turku, Finland, Professor Xxxxxxx X. Xxxx, Glasgow, UK, Professor Xxx Xxxxxxx, Berlin, Germany, Dr. Xxxxxxx Xxxxx, Stockholm, Sweden. Professor Danilo Toni, Rome, Italy, took part in updating the consensus statement and recommendation to the ESO but could not attend the meeting.

Controversy to discuss at the 2010 consensus session:

Is there sufficient evidence to support the conclusion that routine use of intravenous thrombolysis is effective and safe from 3 to 4.5 hours after the onset of stroke symptoms?

Is there sufficient evidence that octogenarians and those with diabetes and prior stroke should be treated with thrombolysis?

What, if any, is the role of multimodal imaging for patient selection for thrombolysis beyond 4.5 hours?

Can intracerebral haemorrhage after thrombolysis be predicted? Background

The second pooled analysis of eight randomised trials[1], confirmed the results of the first pooled analysis[2].

The second pooled analysis included also the EPITHET (100 patients) and ECASS III (821 patients) trials[1,3,4]. The treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as onset to treatment time (OTT) decreased (p=0.0269), and no benefit of alteplase treatment was seen after 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44–4.52) for 0–90 min, 1.64 (1.12–2.40) for 91–180 min, 1.34 (1.06–1.68) for 181–

270 min, and 1.22 (0.92–1.61) for 271–360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted odds of mortality increased with XXX (p=0.0444) and were 0.78 (0.41–1.48) for 0–90 min, 1.13 (0.70–1.82) for 91–180 min, 1.22 (0.87–

1.71) for 181–270 min, and 1.49 (1.00–2.21) for 271–360 min[1].

Interpretation of the investigators:

Patients with ischaemic stroke selected by clinical symptoms and noncontrast CT (nCT) benefit from intravenous alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort should be taken to shorten the delay in initiation of treatment[1].

The essential points of the second pooled analysis compared to the first one are:

– favourable outcome present also for treatment given up to 4.5 hrs, but the odds ratio (OR) for 3 to 4.5 hrs is 1.34 compared to 1.4 in the first pooled analysis.

– “the sooner the better” is strongly confirmed by the OR for good outcome in the 0-90 min interval, with a number needed to treat (NNT) 4.5, as compared to the NNT 14.1 in the 181-270 min interval.

– mortality is associated with the increase of OTT becoming statistically significant after 270 min indicating significant harm for some patients treated in the final OTT interval. However, mortality is not related to symptomatic intracerebral haemorrhage (SICH). In fact, the OR for parenchymal hematoma type 2 (PH2) is always >1 in all time intervals, but with similar absolute rates in all intervals. We consider PH2 instead of SICH as written in the first analysis, since there is not an unequivocal definition of SICH in the different papers, while PH2 is available in all the papers and is the type of ICH more likely to be related to clinical impairment. Hence the adjusted model does not confirm a relation to OTT (and in particular not associated with the 3 to 4.5 h interval), although the low rate of PH2 in some strata limits reliability of the estimation, and the small numbers of PH2 in the placebo group do not allow a statistical adjustment by prognostic factors.

– the “shift analysis”, that is the distribution of alteplase and placebo patients within each category of mRS, confirms the significantly better outcome for patients treated up to 4.5 hrs, but not after 4.5 hrs.

– net benefit is diminishing with time (OR for good outcome decreasing, OR for mortality increasing) and is undetectable beyond 4.5 hrs.

XXXXX XXX enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. The results of ECASS III showed that 219 of 418 patients in the alteplase group (52.4%) had a favourable outcome, which was defined as a score of 0 or 1 on the modified Xxxxxx Scale (mRS) compared with 182 of the 403 patients in the placebo group (45.2%) representing an absolute improvement of 7.2% (OR, 1.34; 95% CI, 1.02 -1.76). In the global analysis of ECASS III data based on the mRS, Xxxxxxx index and the National Institutes of Health Stroke Scale (NIHSS), the outcome was also improved with alteplase when compared with placebo (OR, 1.28; 95% CI, 1.00-1.65). In ECASS III with the extended time window, the NNT for one additional patient to achieve a favourable outcome (mRS 0-1) was 14 [4].

The incidence of intracranial haemorrhage was higher with alteplase than with placebo (for any intracranial haemorrhage, 27.0% vs. 17.6%; p=0.001; for symptomatic intracranial haemorrhage, 2.4% vs. 0.2%; p=0.008). Symptomatic haemorrhage was defined as any intracranial bleeding that was the predominant cause of clinical deterioration, as defined by an increase of 4 points or more in the NIHSS score, or death. In practice, only bleeds of type PH2 fell into this category. In both study groups 29 patients had symptomatic brain oedema. The rate did not differ significantly between the study groups. It was 6.9% in the alteplase group and 7.2% in the placebo group (OR, 0.96; 95% CI, 0.56-1.64). Mortality did not differ significantly between the alteplase and placebo groups (7.7%

and 8.4%, respectively; p=0.68). There was no significant difference in the rate of other serious adverse events[4].

In the post hoc intention to treat analysis adjusted for confounding baseline variables, treatment with alteplase remained significantly associated with a favourable outcome (odds ratio, 1.42; 95% CI, 1.02-1.98; p=0.04)[4].

Interpretation of the investigators:

Intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcome in patients with acute ischaemic stroke when compared with placebo; alteplase was more frequently associated with symptomatic intracranial haemorrhage[4].

SITS-ISTR is a part of SITS collaboration providing information about the safety of thrombolytic treatment in patients treated in a clinical routine setting in agreement with the European marketing licence for alteplase. SITS-ISTR also included off-label use, e.g. when treatment is provided beyond 3 hours. The SITS investigators compared 664 patients with ischaemic stroke treated between 3 and 4.5 hours otherwise compliant with the European summary of the product characteristics criteria with 11 865 patients treated within 3 hours. Outcome measures were SICH defined as PH2 associated with NIHSS > 4 points deterioration, mortality, and independence defined by mRS of 0-2 at 3 months[5].

The data from SITS-ISTR showed that in the 3-4.5-hour cohort, treatment was started on average 55 minutes later after symptom onset (195 min (IQR 187-210) vs. 140 min (IQR 115-165); p<

0.0001), median age was 3 years younger (65 years (55-77) vs. 68 (58-74); p<0.001), and stroke severity was lower (NIHSS score 11 (7-16) vs. 12 (8-17); p<.00001) than in the 3-hour cohort. There were no significant differences between the 3-4.5-hour cohort and the 3-hour cohort for any outcome measures: SICH 2.2% (14 of 649) vs. 1.6% (183 of 11681), OR, 1.18; 95% CI, 0.89-1.55;

adjusted OR, 1.32, 95% CI, 1.00-1.75, mortality 12.7% (70 of 551) vs. 12.2% (1263 of 10368), OR,

1.02; 95% CI, 0.90-1.17; adjusted OR, 1.15; 95% CI, 1.00-1.33, and independence 58.0% (314 of

541) vs. 56.3% (5757 of 10231), OR, 1.04; 95% CI, 0.95-1.13; adjusted OR, 0.93; 95% CI, 0.84-

1.03)[5].

The updated analysis of the 3 to 4.5 hrs cohort of patients in the SITS-ISTR was published in September 2010 in Lancet Neurology. The aims were to assess the implementation of the wider time window and to evaluate its effect on the admission-to-treatment time, as well as safety and functional outcome in patients treated within 3 to 4.5 hrs[6].

23 942 patients were included in the SITS-ISTR registry between December 2002 and February 2010 of whom 2376 were treated within 3-4.5 h after symptom onset. By comparing patients treated before and after October 2008, when XXXXX XXX was published, the proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs. 67 of 1023 [7%]). There was apparently an increase in delayed treatments.

However, also patients treated within 3 hrs increased by 12% in the same period, and had increased by approximately 24% in first quarter of 2009 as compared to the last quarter of 2008.

The median admission-to-treatment time was 65 min both for patients registered before and after October 2008 (p=0.94). In the adjusted analysis there were significant differences as follows: 352 (2%) of 21204 patients treated within 3 h and 52 (2%) of 2317 treated within 3- 4.5 h of stroke had

SICH at 3 months ([OR] 1.44, 95% CI 1.05-1.97; p=0.02). 2287 (12%) of 18583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3-4.5 h had died by the 3-months follow-up (OR 1.26, 95% CI 1.07-1.49;p=0.005). 10531 (57%) of 18317 patients treated within 3 h

of stroke and 1075 (60%) of 1784 who were treated within 3-4.5 h were functionally independent at 3 months (OR 0.84, 95% CI 0.75-0.95; p=0.005)[6].

Interpretation of the investigators:

Since October 2008 thrombolysis within 3–4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes in SITS-ISTR are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier (see table below). Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset[6,7].

The adjusted results of SITS-ISTR with 23 942 patients data were almost identical with those of the SITS analysis 2008[5,6].

	2008 analysis			2010 analysis
	≤ 3 hrs	3 – 4.5	OR	≤ 3 hrs	3 – 4.5 hrs	OR
		hrs	(95%			(95% CI)
			CI)
SICH	183/11681	14/649	1.32	352/ 21204	52/2317	1.44
according to	(1.6%)	(2.2%)	(1.00-	(1.7%)	(2.2%)	(1.05-
SITS-MOST			1.75)			1.97)
SICH	553/11505	34/636	N.A.	1020/21206	121/2304	1.27
according to	(4.8%)	(5.3%)		(4.8%)	(5.3%)	(1.03-
ECASS II						1.55)
SICH	846/11646	52/647	1.13	1515/21245	171/ 2317	1.18
according to	(7.3%)	(8.0%)	(0.97-	(7.1%)	(7.4%)	(0.99-
NINDS			1.32)			1.41)
Mortality 3	1263/10368	70/551	1.15	2287/18583	218/1817	1.26
months	(12.2%)	(12.7%)	(1.00-1-	(12.3%)	(12.0%)	(1.07-
			33)			1.49.)
Mortality 7	751/11621	49/650	N.A.	1307/20956	132/ 2259	1.22
days	(6.5%)	(7.5%)		(6.2%)	(5.8%)	(1.00-
						1.48)
mRS 0-2	5756/10231	314/541	0.93	10531/18317	1075/ 1784	0.84
	(56.3%)	(58.0%)	(0.84-	(57.5%)	(60.3%)	(0.75-
			1.03)			0.95)
mRS 0-1	4084/10231	219/541	N.A.	7467/18 317	793/1784	0.92
	(39.9%)	(40.5%)		(40.8%)	(44.5%)	(0.83– 1.03)

EXTENSION OF THROMBOLYSIS BEYOND A TIME WINDOW OF 4,5 HOURS: THE ROLE OF MULTIMODAL IMAGING

The statement is based on four major data sources: the EPITHET data, the DEFUSE data, the DIAS2 data, and the recent meta-analysis of delayed thrombolysis [3,8-10].

Background:

The current evidence for the time dependent benefit of IV thrombolysis is based on randomised clinical trials (RCTs) using noncontrast Computed Tomography (nCT) as the imaging modality of choice. Accordingly, the guidelines recommend IV thrombolysis up to 4,5 hours after symptom

onset by the use of nCT. In the pooled analysis, IV thrombolysis beyond 4,5 h was associated with a higher shown significant increased risk of mortality, with a lower chance of clinical recovery after 3 months and showed a trend to higher rates of treatment related bleeding[1].

However, several studies suggest that multimodal imaging techniques yield a valuable pathophysiological characterisation of ischaemic stroke[3,8,9]. The presence of irreversibly damaged tissue (“infarct core”) and of hypoperfused but still viable tissue (“penumbra”) in the first hours after ischaemic stroke has been demonstrated by case series using positron emission tomography (PET). In the clinical setting this concept has been translated to the concept of “mismatch” using DW/PW-MRI and perfusion-CT. Mismatch defines the volumetric ratio of at least 1,2 between the hypoperfusion (defined by PWI) and the infarct core (defined by DWI).

Alternatively, perfusion CT can be used for mismatch definition keeping in mind several methodological differences.

Current data:

The assessment of mismatch in acute stroke bears the promise to identify the subgroup of patients that might benefit from reperfusion/recanalisation beyond 4,5 h after symptom onset. Observational studies suggest, that IV thrombolysis beyond 4,5 h using the mismatch criteria might be comparable to nCT based thrombolysis within 3 h with respect to safety and efficacy. However, evidence from RCT is still scant, and the mismatch criteria need to be standardised.

Two clinical trials of multimodal MR imaging using alteplase for IV thrombolysis 3 to 6 hours after stroke are available. In both studies, however, the therapeutic decision for IV thrombolysis was drawn by noncontrast CT. The DEFUSE trial suggested that MRI might identify mismatch patterns that respond favourably to thrombolysis. However, this study included only 74 patients and had no control group[8]. The EPITHET trial included 101 patients in a prospective placebo controlled randomised design. It found a significantly increased reperfusion rate in mismatch patients and better outcome in patients with reperfusion[3]. However, the reduction of infarct growth was not significant. The only RCT in which patients for thrombolysis were selected according to mismatch criteria, the DIAS II trial[9], used desmoteplase and included 193 patients (n=122 stroke MRI; n=64 perfusion CT). Although specific issues of the trial are currently under discussion, a benefit of thrombolysis beyond 4,5 h according mismatch criteria could not be shown. Accordingly, a recent meta-analysis, including 502 patients from DEFUSE, EPITHET and DIAS (as well as the precursor studies DIAS and DEDAS) with IV thrombolysis beyond 3 hours, summarizes that the imaging based mismatch selection of patients for IV thrombolysis beyond 4,5 h can at present not be recommended as a part of routine care[10]. Even though delayed thrombolysis in mismatch patients was associated with an increased rate of reperfusion and even though reperfusion was associated with improved outcome, the mismatch based selection of patients for delayed thrombolysis did not significantly improve outcome.

Conclusions:

Although the current data suggest that multimodal imaging might help to identify patients that benefit from IV thrombolysis beyond 4,5 h, the current evidence is not strong enough to recommend reliance on this patient-selection for routine care. Nevertheless, the data are in favour of further investigations in RCT. The correct definition of the “tissue at risk” seems crucial to apply this concept to acute stroke patients.

Main issues needing to be clarified include:

– the choice of the adequate perfusion imaging parameters [11]

– the performance of mismatch imaging with respect to the tissue at risk [12]

– the adequate definition of mismatch [13,14]

– the problem of DWI reversibility [15]

– the comparison of multimodal CT and MRI in imaging the tissue at risk [16]

– the additional value of FLAIR imaging for patient selection [17]

The ongoing studies EXTEND, DIAS-3 and -4, and ITAIS-2 will shed more light on this multimodal imaging approach.

Data on the safety and efficacy of thrombolysis in octogenarians and those with diabetes and earlier stroke

Data on the safety and efficacy of thrombolysis in octogenarians, those with diabetes and earlier stroke i.e. the off-label use of alteplase is based on SITS and SITS-ISTR registries, on controlled comparisons within and against VISTA, and on open non-randomised case series[5,6,18,19,20,389] with only limited data from randomised trials.

Adjusted analysis of the limited randomised data in patients above 80 years is consistent with similar benefit and risk as in patients under 80 years. While some registries have found poorer outcomes in octogenarians than in younger patients treated with IV alteplase[21-23] other registries[20,24] and controlled studies have shown that the treatment benefit of IV alteplase in patients aged over 80 years is similar to that in younger patients[19,25] and registries have not shown significant increased risk of symptomatic hemorrhage[26].

A non-randomised controlled comparison and a registry in patients with diabetes and prior stroke found similar benefit as in patients without stroke or diabetes[18,24].

In due course, the ongoing IST-3 and the TESPI trial will supplement these data. IST 3 result will be presented at ESO Congress , Lisbona May 2012.

DISCUSSION

The results of ECASS III and the SITS-ISTR registry study showed that intravenous alteplase given between 3 and 4.5 hours (median 3 hours 59 minutes in ECASS III and 3 hours 15 minutes in SITS- ISTR registry) after stroke onset is associated with an improvement in clinical outcome (absolute difference 7.2% and NNT up to 14 in ECASS III), in patients who otherwise meet the licensing criteria, without a higher rate of SICH than reported previously among patients treated within 3 hours. The effect size of thrombolysis is time-dependent. The shift analysis of the distribution of alteplase and placebo patients within each category of mRS showed the significant better outcome for patients treated up to 4.5 hrs, but not after 4.5 hrs[4,5].

The results of the second pooled analysis confirmed that intravenous alteplase started between 3 and

4.5 hours after stroke onset is effective, although the net benefit decreases with time due to decrease of odds for good outcome and increase of odds for mortality which becomes significant after 270 minutes. The risk of symptomatic intracranial hemorrhage does not significantly increase with time[1].

The results of the SITS-ISTR registry showed that the extension of the time window to 4.5 hours led to an increase of treatments in the time interval 3 to 4.5 hours but also of treatments within 3 hours, and that admission to treatment times did not increase. Rates of symptomatic intracranial

hemorrhage and mortality were higher and good outcome less frequent in the later cohort, but these outcomes have remained constant for several years[6].

The effect size of thrombolysis is time-dependent. The NNT to get one more favourable outcome drops from 4.5 during the first 90 minutes, through 9 within 3 hours and towards 14 between 3 and

4.5 hours[1]. Early treatment remains essential but a longer time window offers an opportunity for patients who cannot be treated within the previously approved 3-hour time window. The results of ECASS III, of the second pooled analysis and SITS-ISTR registry should not slow down the efforts to facilitate early treatment. Patients should be treated as early as possible to maximize the benefit. The value of multimodal imaging for thrombolysis beyond 4.5 hours is still under investigation. The possibility of imaging based patient stratification has been described in various non randomised studies and has shown promising results. However, the current evidence from clinical trials[3,8,9] is not strong enough to imply multimodal imaging in routine care and ongoing studies have to be awaited[10].

Although some registries have found poorer outcomes in octogenarians than in younger patients[21- 23], other registries[20] and controlled comparisons have suggested that treatment benefit in octogenarians is similar to that in younger patients[19,25] and registries have not shown significant increased risk of symptomatic hemorrhage[26]. Treatment of very elderly is reasonable and may be offered unless the patient is prepared to enter an RCT, or unless the marketing approval restrictions prevent this locally.

A non-randomised controlled comparison and a registry in patients with diabetes and prior stroke found similar benefit as in patients without stroke or diabetes[18,24].

CONCLUSIONS

The results of ECASS III, the second pooled, analysis and the SITS-ISTR registry confirm the conclusion drawn from the pooled data from prior RCTs, that intravenous alteplase started between 3 and 4.5 hours after symptom onset is effective, and that although the risk of intracranial haemorrhage is increased compared to placebo, this treatment from 3 up to 4.5 hours remains safe and effective.

The current evidence supports the use of IV thrombolysis in patients aged over 80 years as well as in diabetic patients with prior stroke if they otherwise fulfill treatment criteria.

Multimodal imaging might be helpful in the identification of patients that can benefit from IV thrombolysis beyond 4.5 h but the current evidence is not sufficient to implement imaging based selection for delayed thrombolysis in routine care.

REFERENCES

Xxxx KR, Xxxxxxx E, xxx Xxxxxx R, Xxxxx TG, Xxxx D, Xxxxxx JC, Xxxxxx GW, Xxxxx M, Xxxxxx XX, Xxxxxxxx SA, Xxxxxx BC, Xxxxx SM, Xxxxxx XX, Xxxxx W; ECASS, XXXXXXXX, XXXXX and EPITHET rt-PA Study Group, Xxxxx K, Xxx J, Xxxxx D, xxx Xxxxx X, Xx Xxxxx DA, Xxxxxxx KS, Xxxxxxx MW, Xxxxxx PA, Xxxx C, Xxxxxx C, Xxxxxx G. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695-703.

Xxxxx W, Xxxxxx X, Xxxxxxx C, Xxxxx M, xxx Xxxxxx R, Xxxxxxxxx JP, Xxxxx T, Xxxxxxx M, Xxxxxx JC, Xxxxx XX Xx, Xxxxxxxxxxx T, Xxxxxx SR, Xxxxxxxxxxx C, Xx M, Xxxxx P, Xxxxxx XX, Xxxxx S, Xxxxxx BC, Xxxxxx G: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and XXXXX rt-PA stroke trials. Lancet 2004;363:768-74.

Xxxxx SM, Xxxxxx XX, Xxxxxxx MW, Xxxx C, Xxxxxxx KS, Xxxxxxx A, Xxxxxx PA, Xxxxxx C, Xx Xxxxx DA, Xxxxxx G, Xxxxx JB, Xxxx XX, Xxxxxx TE, Xxxxxxx D, Xxxx PJ, Xxxxxx J, Xxxxxx G, Xxxx K, Xxxxxxx R, Xxxxx BM, Xxxxxxx PM; EPITHET investigators. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo- controlled randomised trial. Lancet Neurol 2008;7:299-309.

Xxxxx W, Xxxxx M, Xxxxxxx E, Xxxxxxx M, Xxxxxxx A, Xxxxxxxx D, Xxxxxx V, Xxxx KR, Xxxxxxxx Z, Xxxxxxx T, Schneider D, xxx Xxxxxx R, Xxxxxxxx N, Xxxx X, for the ECASS Investigators.

Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New Engl J Med 2008;359:1317-29.

Xxxxxxxx N, Xxxxx N, Xxxxxxx A, Xxxxx W, Xxxxxx M, Xxxx K, Xxxxx RO, Xxxx X, Xxxx KR. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008;372:1303-9.

Xxxxx X, Xxxxxxxx X, Xxxxx X, Xxxxxxxxx X, Xxxx XX, Xxxxxxx R, Xxxxxxx M, Xxxxx RO, Xxxx X, Xxxxxxx P, for the SITS investigators. Implementation and outcome of thrombolysis with alteplase 3–4·5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol 2010;9:866-74.

Strbian D, Xxxxxx L, Xxxxxxxx T, Häppölä O, Xxxxxxxxx PJ, Tatlisumak T, Kaste M; Helsinki Stroke Thrombolysis Registry Group. Ultraearly thrombolysis in acute ischemic stroke is associated with better outcome and lower mortality. Stroke 2010;41:712-6.

Xxxxxx GW, Xxxxx VN, Xxxxxxxx L, Xxxx S, Xxxxxxx G, Xxxxxxxxx E, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. 2006 Nov;60(5):508- 17.

Hacke W, Furlan AJ, Al-Rawi Y, Xxxxxxx A, Fiebach JB, Xxxxxx F, Xxxxx M, Xxxxx LJ, Xxxxxxx S, Xxxxxxx PA, Xxxxxx HA, Schneider D, Xxxxxxx LH, Xxxx JS, Xxxxxxx M, Xxxx PA, Xxxxxxx- Ogunbiyi K, Xxxxxxxxxx M, Warach S. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009;8:141-50.

Xxxxxx NK, Xxxxxx GW, Xxxxx SM, Xxxxxx GA, Xxxxxx AJ, Xxxxx W, Xxxx KR. Mismatch-based delayed thrombolysis: a meta-analysis. Stroke 2010;41:e25-33. Erratum in: Stroke 2010;41:e399. Xxxx-Xxxxx O, Xxxxxxx-Xxxxxxxx W, Xxxxx WD, Xxxxxxx J. MRI perfusion maps in acute stroke validated with 15O-water positron emission tomography. Stroke. 2010 Mar;41(3):443-9. Epub 2010 Xxx 14.

Xxxxxxx J, Xxxx Xxxxx O, Xxxxxxxxx FG, Xxxxxxxxxx V, Xxxxxxxx M, Xxxxxx A, Xxxxx WD. Does the mismatch match the penumbra? Magnetic resonance imaging and positron emission tomography in early ischemic stroke. Stroke 2005;36:980-5.

Xxxxxx W, Xxxxxxxx MG, Xxxxx VN, Xxxx SM, Xxxxxx R, Xxxxxxxx LR, et al. Optimal definition for PWI/DWI mismatch in acute ischemic stroke patients. J Cereb Blood Flow Metab 2008;28:887- 91.

Xxxxxxxx BC, Xxxxxxxxxxx S, Xxxxxx SJ, Xxxxxxx PM, Xxxxxxx MW, Xxxxxxx KS,Xxxxxx PA, Xxxx CR, Xxxxxx CF, Xxxxxx XX, Xxxxx SM; EPITHET Investigators. Visual assessment of perfusion- diffusion mismatch is inadequate to select patients for thrombolysis. Cerebrovasc Dis.

2010;29(6):592-6. Epub 2010 Apr 14. PubMed PMID: 20389068.

Xxxxx PG, Xxxxxxxx JD. Does diffusion-weighted imaging represent the ischemic core? An evidence-based systematic review. Am J Neuroradiol 2009;30:1206-12. Erratum in: Am J Neuroradiol 2009;30:E114. assessment of mismatch (e.g. Xxxxxxxx 2010)

Xxxxxxxx PW, Xxxxx ER, Kamalian S, Xxxxxx LR, Xxxxxxx L, Xxxxxxxx RG, Xxx MH. Quantitative assessment of core/penumbra mismatch in acute stroke: CT and MR perfusion imaging are strongly correlated when sufficient brain volume is imaged. Stroke 2008;39:2986-92.

Xxxxxxxx G, Xxxxxxxx P, Xxxxxxxxxx M, Xxxxxxxxx S, Xxxxxxxxxxx A, Xxxxxxx J, Xxxxxxx C. Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or less. Xxx Xxxxxx 2009;65:724-32.

Xxxxxx XX, Xxxxx X, Xxxxxxxx G, Xxxxx JA, Xxxxxxxxx PJ, Xxxxxxx PA, Xxxxxxxx NG, Lees KR for SITS and VISTA Collaborators Thrombolysis in very elderly people: controlled comparison of SITS International Stroke Thrombolysis Registry and Virtual International Stroke Trials Archive BMJ 2010 341:c6046 (+ ONLINE PUBLICATION in press)

Xxxxxx XX, Xxxxx XX, Xxxxx X, Xxxx XX for VISTA Collaborators. Comparison of outcomes following thrombolytic therapy amongst patients with prior stroke and diabetes in the Virtual International Stroke Trials Archive (VISTA). Diabetes Care 2010. (in press)

Xxxxxx XX, Xxxxxx AM, Xxxx MD; CASES Investigators. Outcomes of thrombolysis for acute ischemic stroke in octogenarians versus nonagenarians. Stroke 2010;41:1833-5.

Alshekhlee A, Xxxxxxxxx A, Xxxxx S, Xxxxxx RC, Xxxx N, Xxxx E, Xxxx S, Xxxxxx ZA, Xxxx- Xxxxxx S. Is thrombolysis safe in the elderly?: analysis of a national database. Stroke 2010;41:2259- 64.

Xxxxxxxxxx WT Jr, Xxxx R, Xxxxxxxxxx DL, Xxxxxxx M, Xxxxx BM. Intravenous tissue plasminogen activator and stroke in the elderly. Am J Emerg Med 2010;28:359-63.

Xxxxxx P, Xxxxxxxxxxx DO, Xxxxxx SD, Xxxxx JL, Xxxxxx XX, Xxxxx PD, Xxxxxx CJ, Xxxxxxx YY, Xxxxx EC, Xxxxxxxxx JP. Strokes with minor symptoms: an exploratory analysis of the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator trials.

Stroke 2010;41:2581-

Meretoja A, Xxxxxxx J, Xxxxxxxxxx T, Xxxxx S, Xxxxx V, Xxxxxx S, Häppölä O, Xxxxxxxxx PJ, Xxxxxxxxx S, Xxxxxxxx K, Xxxxxxxxxx J, Xxxxxxxx K, Xxxxxxxx T, Xxxxxxx O, Silvennoinen H, Xxxxxx L, Xxxxxxx D, Xxxxxxx M, Kaste M. Off-label thrombolysis is not associated with poor outcome in patients with stroke. Stroke 2010;41:1450-8.

Xxxxxx XX, Xxxxxx XX, Xxxxx XX, Xxxxxxx X, Xxxx XX; for the VISTA Collaborators. Influence of Age on Outcome From Thrombolysis in Acute Stroke. A Controlled Comparison in Patients From the Virtual International Stroke Trials Archive (VISTA). Stroke 2010 Oct 2010; doi:10.1161/STROKEAHA.110.586206 (in press)

Xxxx XX, Xxxxx X, Xxxxxxx E, Xxxxx X, Xxxxxx X, Xxxxxxxxx PJ, Xxxx X, Xxxxxxxx N. Intravenous alteplase for stroke in those older than 80 years old. Stroke 2010 ;41:2568-74.

II. RECOMMENDATION BY KAROLINSKA STROKE UPDATE PARTICIPANTS TO ESO GUIDELINES COMMITTEE TO REVISE ESO GUIDELINES

Specific treatment: thrombolysis RECOMMENDATIONS

Intravenous rtPA (0.9 mg/kg body weight, maximum 90 mg), with 10% of the dose given as a bolus followed by a 60-minute infusion, is recommended within 3 hours of onset of ischaemic stroke (Class I, Level A)

There is clear evidence that intravenous rtPA is beneficial if given between 3 and 4.5 hours after stroke onset (Class I, Level A). It is recommended that treatment is considered in patients who otherwise meet the licence criteria.

The use of multimodal imaging criteria may be useful for patient selection for thrombolysis (Class III, Level C) but is not recommended for routine clinical practice (Class II, Level B)

It is recommended that blood pressures of 185/110 mmHg or higher is lowered before thrombolysis (Class IV, GCP)

It is recommended that intravenous rtPA may be used in patients with seizures at stroke onset, if the neurological deficit is related to acute cerebral ischaemia (Class IV, GCP)

It is recommended that intravenous rtPA may also be administered in selected patients under 18 years and over 80 years of age, although this is outside the current European labeling (Class III, Level C)

It is recommended that intravenous rtPA may also be administered in selected patients who have diabetes mellitus and have suffered prior stroke, although this is outside the current European labeling (Class III, Level C)

Intra-arterial treatment of acute MCA occlusion within a 6-hour time window is recommended as an option (Class II, Level B)

Intra-arterial thrombolysis is recommended for acute basilar occlusion in selected patients (Class III, Level B). Intravenous thrombolysis for basilar occlusion is an acceptable alternative even after 3 hours (Class III, Level B)

It is recommended that aspirin (160–325 mg loading dose) be given within 48 hours after ischaemic stroke (Class I, Level A)

It is recommended that if thrombolytic therapy is planned or given, aspirin or other antithrombotic therapy should not be initiated within 24 hours (Class IV, GCP)

The use of other antiplatelet agents (single or combined) is not recommended in the setting of acute ischaemic stroke (Class III, Level C)

The administration of glycoprotein-IIb-IIIa inhibitors is not recommended (Class I, Level A) Early administration of unfractionated heparin, low molecular weight heparin or heparinoids is not reommended for the treatment of patients with acute ischaemic stroke (Class I, Level A) Currently, there is no recommendation to treat ischaemic stroke patients with neuroprotective substances (Class I, Level A)

ADDITION TO TEXT:

Thrombolytic therapy:

The European Cooperative Acute Stroke Study III (ECASS III) showed that intravenous alteplase administered between 3 and 4.5 hours (median 3 h 59 min) after the onset of symptoms significantly improves clinical outcomes in patients with acute ischemic stroke compared to placebo[1]; the absolute improvement was 7.2% and the adjusted OR of favourable outcome (mRS 0-1) was 1.42, 1.02-1.98. Mortality did not differ significantly (7.7% versus 8.4%), but alteplase increased the risk of SICH (2.4% vs. 0.2%). Treatment benefit is time-dependent. The number needed to treat to get one more favourable outcome drops from 4.5 during the first 90 minutes through 9 within 3 hours and towards 14 between 3 and 4.5 hours[5].

The SITS investigators compared 664 patients with ischaemic stroke treated between 3 and 4.5 hours otherwise compliant with the European summary of the product characteristics criteria with 11 865 patients treated within 3 hours. In the 3-4.5-hour cohort, treatment was started on average 55 minutes later after symptom onset. There were no significant differences between the 3-4.5-hour cohort and the 3-hour cohort for any outcome measures, confirming that alteplase remains safe when given between 3 and 4.5 hours after the onset of symptoms in ischaemic stroke patients who otherwise fulfil the European summary of product characteristics criteria[2].

More recently the SITS investigators extended the analysis by comparing 2376 patients treated between 3 and 4.5 hours with 21 566 patients treated within 3 hours, of whom those reported in the previous analysis are a part. In the updated analysis 23 942 patients were included in the SITS-ISTR registry between December 2002 and February 2010 of whom 2 376 were treated within 3-4.5 h after symptom onset. The proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs. 67 of 1023 [7%]). The median admission-to-treatment time was 65 min both for patients registered before and after October 2008 (p=0.94). In the adjusted analysis there were significant differences as follows: 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2 317 treated within 3- 4.5 h of stroke had

SICH at 3 months ([OR] 1.44, 95% CI 1.05-1.97; p=0.02). 2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1 817 who were treated within 3-4.5 h had died by the 3-month follow-up (OR 1.26, 95% CI 1.07-1.49;p=0.005); 10 531 (57%) of 18 317 patients treated within 3

h of stroke and 1 075 (60%) of 1 784 who were treated within 3-4.5 h were functionally

independent at 3 months (OR 0.84, 95% CI 0.75-0.95; p=0.005)[3].

The updated cohort studied in this new analysis made the differences between patients treated within 3 hours and those treated between 3 and 4.5 hours statistically significant in favour of earlier treatment, although the absolute rates of symptomatic intracranial haemorrhages, mortality and functional independence in the two time intervals were similar and quite overlapping to those of the previous report. Admission to treatment times were not increased after the implementation of the 3 to 4.5 hour time window[3]. Interpretation of the investigators: Since October 2008 thrombolysis within 3–4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset[3,4].

Pooled analysis of individual patient data from the randomised trials of intravenous alteplase of acute ischaemic stroke confirms a favourable risk-benefit profile until 4.5 hours after stroke onset, but later initiation of treatment is associated with increased 3-month mortality and no significant benefit[5]. Treatment benefit is time-dependent. The net benefit decreases with time due to decrease of odds for good outcome and increase of odds for mortality, which becomes significant after 270 minutes. The risk of symptomatic intracranial haemorrhage does not increase with time. The

number needed to treat to get one more favourable outcome drops from 4.5 during the first 90 minutes, through 9 within 3 hours and towards 14 between 3 and 4.5 hours[5].

The value of multimodal imaging for thrombolysis beyond 4.5 hours is still under investigation. The possibility of imaging based patient stratification for delayed thrombolysis has been shown in non randomised studies with promising results[44,45]. However, the adequate definition of the tissue at risk using multimodal MRI or CT is still lacking[6-12]. The current evidence from clinical trials of delayed thrombolysis[13,14,15] is promising but not strong enough to implement multimodal imaging in routine care[16] and ongoing studies have to be awaited.

Although some registries have found poorer outcomes in octogenarians than in younger patients[17- 19], other registries[20] and controlled comparisons have suggested that treatment benefit in the octogenarians is similar to that in younger patients[21,22] and registries have not shown significant increased risk of symptomatic haemorrhage[23]. Treatment of patients aged over 80 years is reasonable and may be offered unless the patient is prepared to enter an RCT, or unless the marketing approval restrictions prevent this locally.

A non-randomised controlled comparison and a registry in patients with diabetes and prior stroke found similar benefit as in patients without stroke or diabetes [24,25].

NEW REFERENCES:

Xxxxx W, Xxxxx M, Xxxxxxx E, Xxxxxxx M, Xxxxxxx A, Xxxxxxxx D, Xxxxxx V, Xxxx KR, Xxxxxxxx Z, Xxxxxxx T, Schneider D, xxx Xxxxxx R, Xxxxxxxx N, Xxxx X, for the ECASS Investigators.

Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New Engl J Med 2008;359:1317-29.

Xxxxxxxx BC, Xxxxxxxxxxx S, Xxxxxxx KS, Xxxxxx I, Xxxxxxx MW, Xxxxxxx PM, Xxxxxx PA, Xxxx CR, Xxxxxx CF, Xx Xxxxx DA, Xxxxxx XX, Xxxxx SM; EPITHET Investigators. Regional very low cerebral blood volume predicts hemorrhagic transformation better than diffusion-weighted imaging volume and thresholded apparent diffusion coefficient in acute ischemic stroke. Stroke. 2010;41:82- 8.

Xxxx-Xxxxx O, Xxxxxxx-Xxxxxxxx W, Xxxxx WD, Xxxxxxx J. A simple positron emission tomography-based calibration for perfusion-weighted magnetic resonance maps to optimize penumbral flow detection in acute stroke. Stroke 2010;41:1939-45.

Xxxxxx W, Xxxxxxxx MG, Xxxxx VN, Xxxx SM, Xxxxxx R, Xxxxxxxx LR, et al. Optimal definition for PWI/DWI mismatch in acute ischemic stroke patients. J Cereb Blood Flow Metab 2008;28:887- 91.

Xxxxxx NK, Xxxxxx GW, Xxxxx SM, Xxxxxx GA, Xxxxxx AJ, Xxxxx W, Xxxx KR. Mismatch-based delayed thrombolysis: a meta-analysis. Stroke 2010;41:e25-33. Erratum in: Stroke 2010;41:e399. Alshekhlee A, Xxxxxxxxx A, Xxxxx S, Xxxxxx RC, Xxxx N, Xxxx E, Xxxx S, Xxxxxx ZA, Xxxx- Xxxxxx S. Is thrombolysis safe in the elderly?: analysis of a national database. Stroke 2010;41:2259- 64.

Xxxxxxxxxx WT Jr, Xxxx R, Xxxxxxxxxx DL, Xxxxxxx M, Xxxxx BM. Intravenous tissue plasminogen activator and stroke in the elderly. Am J Emerg Med 2010;28:359-63.

Stroke 2010;41:2581-6.

Xxxxxx XX, Xxxxxx AM, Xxxx MD; CASES Investigators. Outcomes of thrombolysis for acute ischemic stroke in octogenarians versus nonagenarians. Stroke 2010;41:1833-5.

Xxxxxx XX, Xxxxx X, Xxxxxxxx X, Xxxxx XX, Xxxxxxxxx XX, Xxxxxxx XX, Xxxxxxxx NG, Lees KR for SITS and VISTA Collaborators Thrombolysis in very elderly people: controlled comparison of SITS International Stroke Thrombolysis Registry and Virtual International Stroke Trials Archive BMJ 2010 341:c6046 (+ ONLINE PUBLICATION in press)

Xxxx XX, Xxxxx X, Xxxxxxx E, Xxxxx X, Xxxxxx X, Xxxxxxxxx PJ, Xxxx X, Xxxxxxxx N. Intravenous alteplase for stroke in those older than 80 years old. Stroke 2010 ;41:2568-74.

EXISTING REFERENCES:

26. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. New Engl J Med 1995;333:1581-1587.

27. Xxxxxxx J, Xxxxxxx C, Xxxxxxxx L, Xxxx M, Xxxxxxx J, Xxxxxxx X, Xxxx X, Xxxxxxxx X, Xxxxxx X, Xxxxxx X: Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet 2007;369:293-298.

28. Xxxx I, Xxxxxxxxxx P, Xxxxxxx J: Magnetic resonance perfusion diffusion mismatch and thrombolysis in acute ischaemic stroke: a systematic review of the evidence to date. JNNP 2007;78:485-490.

29. Xxxxxx GW, Xxxxx VN, Xxxxxxxx L, Xxxx S, Xxxxxxx G, Xxxxxxxxx E, Xxxxxx R, Xxxxxx W, Xxxxxxxx MG, Xxxxxx A, Xxxxxx W, Xxxxxxxx S, Xxxxxxx M, Xxxxx MP: Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Xxx Xxxxxx 2006;60:508-517.

30. Xxxxx W, Xxxxx M, Xxxxxxx C, xxx Xxxxxx R, Xxxxxxx A, Xxxxx D, Xxxxxx V, Xxxxxxx E, Xxxxx S, Xxxxxx G, Xxxxxxxx D, Diez-Tejedor E, Xxxxxxxx P: Randomised double-blind placebo- controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998;352:1245-1251

31. Xxxxx W, Xxxxx M, Xxxxxxx C, Xxxx D, Lesaffre E, xxx Xxxxxx R, Xxxxxx G, Xxxxxxx E, Höxter G, Xxxxxxx MH, Xxxxxxxxx M: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute stroke. JAMA 1995;274:1017-1025.

32. Xxxxx W, Xxxxxx X, Xxxxxxx C, Xxxxx M, xxx Xxxxxx R, Xxxxxxxxx JP, Xxxxx T, Xxxxxxx M, Xxxxxx JC, Xxxxx XX Xx, Xxxxxxxxxxx T, Xxxxxx SR, Xxxxxxxxxxx C, Xx M, Xxxxx P, Xxxxxx XX, Xxxxx S, Xxxxxx BC, Xxxxxx G: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and XXXXX rt-PA stroke trials. Lancet 2004;363:768-774

33. Sylaja PN, Cote R, Xxxxxx AM, Xxxx MD: Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry 2006;77:826-829.

34. xxx Xxxxxxxxxxxx RJ, Xxxxxxxx RM, Xxxxxx J: Thrombolysis for acute stroke with special emphasis on the very old: experience from a single Dutch centre. J Neurol Neurosurg Psychiatry 2006;77:375-377.

35. Xxxxxxx PA, Xxxxxxx C, Xxxxxxxx M, Xxxxxxx S, Xxxxxxx E, Xxxxx W, Xxxxxxxxxxx PD: Thrombolytic therapy for acute ischaemic stroke in octogenarians: selection by magnetic resonance imaging improves safety but does not improve outcome. J Neurol Neurosurg Psychiatry 2007;78:690-693.

36. Xxxx MD, Xxxxxx AM: Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study (CASES). CMAJ 2005;172:1307-1312.

37. Xxxxxxx BT, Xxxxxxxxxx HC, Xxxxx-Xxxxxx B, Xxxxxx MF, Xxxx JP, Xxxxx RL, Pile- Xxxxxxxx J: Factors associated with in-hospital mortality after administration of thrombolysis in acute ischemic stroke patients: an analysis of the nationwide inpatient sample 1999 to 2002. Stroke 2006;37:440-446.

38. Xxxxxxxx N, Xxxxx N, Xxxxxxx A, Xxxx GA, Xxxxx X, Xxxxx W, Xxxxxxxxx MG, Xxxxx M, Xxxxxxx S, Xxxxxx V, Xxxx KR, Xxxxx RO, Xxxxxx L, Xxxx X, Xxxxxxxxx G: Thrombolysis with

alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke- Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282.

39. Xxxxxx IL, Xxxxxx MD, Xxxxxx AJ, Xxxxxx ED, Nadzam DM: Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke 2003;34:799-800.

40. Xxxxxx GD: Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta- analysis of safety data. Stroke 2003;34:2847-2850

41. Xxxxxxxxxx AV, Xxxxxx CA, Xxxxxx JC, Xxxxxx Z, Xxxx SR, Xxxxxxx-Xxxxx J, Xxxxxxxx J, Xxxxxx M, Xxxxxxx AM, Xxxx LA, Xxxx MD, Wojner AW: Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004;351:2170-2178.

42. Xxxxxx CA, Xxxx M, Xxxxxxx M, Xxxxxxxx J, Xxxxxxxxxxx E, Xxxxxxx-Xxxxxxx R, Xxxxxxxxx JF, Xxxxxxx R, Xxxxxx F, Xxxxxxx P, Xxxxxxx-Xxxxx J: Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006;37:425-429.

43. Xxxxxxxx M, Xxxxxxx E, Xxxxxxx JB, Xxxxxxx HB, Xxxxxxx S, Xxxxxxx C, Xxxxxxx PA, Xxxxxxxxxxx PD, Xxxxx W: MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study. Lancet Neurol 2006;5:661-667.

44. Xxxxxxxxxxx PD, Xxxxxxxx G, Xxxxxxx J, Xxxxxxxx M, Xxxxxx CA, Xxxxxxx-Xxxxxxxx T, Xxxx M, Xxxxxx OC, Xxxx-Xxxxx O, Xxxxxxx J: MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1,210 patients. Stroke 2007;38:2640-2645.

45. Xxxxxxxx MG, Xxxxx VN, Xxxxxx R, Xxxx S, Xxxxxx CA, Xxxxx MP, Xxxxxx GW: Risk factors of symptomatic intracerebral hemorrhage after tPA therapy for acute stroke. Stroke 2007;38:2275-2278

PROCEDURA APPLICATIVA

Il 118 in caso di sospetto ictus contatta il medico di guardia della Neurologia (32545) e/o quella della Stroke Unit (32549, questo dalle 9-14.30 al momento), in base alla discussione del caso si attiverà il codice stroke. Il paziente viene pertanto centralizzato presso il PS di Baggiovara, avvertito dal 118. In caso di accesso diretto sarà il personale del triage del PS ricevente a contattare il medico della Neurologia.

All’arrivo in PS, il medico di PS, valuta il paziente avverte immediatamente il Neurologo di guardia, se non è già in PS. Nel caso in cui il paziente sia eligibile per la trombolisi viene avvertito il medico della Stroke Unit (al momento presente fino alle 14.30). Quest’ultimo prenderà in carico il paziente e valuterà l’eventuale scenario da applicare. Nel frattempo in PS verranno effettuati: registrazione parametri vitali, prelievo ematico secondo profilo ictus (emocromo, INR, aPTT, fibrinogeno, didimero, glicemia, creatinina, urea, sodiemia, kaliemia), accesso venoso periferico, ECG, valutazione del quadro neurologico mediante calcolo NIHSS, TAC encefalo di base (per escludere lesioni emorragiche) ed eventuale completamento con angioTAC extra-intracranica e TC perfusion in base al quadro clinico e seguendo le indicazioni del protocollo e discussione del caso Neurologo-Neuroradiologo.

Durante tutto il percorso diagnostico in PS e la successiva decisione terapeutica, il Neurologo avrà il compito di informare il paziente e i famigliari, del quadro clinico, dei risultati degli accertamenti e delle possibilità terapeutiche. Verrà inoltre acquisito dal paziente quando possibile il consenso informato, in altri casi si applicherà il principio dello stato di emergenza, previa informazione completa dei famigliari.

Al termine di tali accertamenti che dovranno avvenire nel più breve tempo possibile (“time is brain”, obiettivo door-to-needle <60 minuti), verrà stabilita la terapia più idonea e il paziente sarà ricoverato in Stroke Unit. A questo punto si hanno due possibili scenari:

A. Il paziente candidato a terapia trombolitica endovenosa verrà direttamente ricoverato in Stroke Unit e secondo procedura.

B. Il paziente candidato a trombolisi intra-arteriosa andrà direttamente dal Pronto Soccorso in sala angiografica. Il medico di PS chiude la pratica di PS con ricovero in Stroke Unit su SIO e relativa diagnosi di ammissione. Il personale infermieristico del PS pazienti prima del trasporto in sala angiografica dovranno verificare il posizionamento e pervietà del catetere vescicale e verificare la presenza e pervietà di due accessi venoso periferici). Il Neuroradiologo interventista dovrà attivare la procedura di urgenza in sala angiografica che prevede:

- disponibilità sala angiografica

- presenza del tecnico di neuroradiologia

- presenza dell’infermiere di sala

- avvertire nel frattempo il Neurorianimatore la cui presenza è necessaria in sala angiografica. Il paziente dovrà essere accompagnato in sala angiografica dal Neurologo di guardia (o dal Neurologo della Stroke Unit se presente). In sala angiografica dovranno essere presenti il Neurorianimatore e il Neurologo in modo da collaborare con il Neuroradiologo durante la procedura. Il Neurologo inoltre valuterà clinicamente il paziente, compilerà la cartella clinica oltre ad intervenire nelle decisioni terapeutiche. Al termine della procedura verrà effettuata TC encefalo di controllo per escludere sanguinamenti.

Al termine della procedura angiografica se non si sono verificate complicanze e il paziente non è stato sedato e/o intubato verrà trasportato in Stroke Unit, e monitorato secondo protocollo trombolisi.

Nel caso di complicanze in particolare respiratorie o in caso di sedazione il paziente verrà trasferito in Neurorianimazione, monitorato secondo protocollo trombolisi. Il Neurologo della Stroke Unit valuterà giornalmente il paziente per impostare in accordo con il neuro rianimatore il percorso diagnostico terapeutico fino al ri-trasferimento in Stroke Unit.

VALUTAZIONE DEGLI ESITI

Indipendentemente dagli SCENARI di tutti i pazienti saranno valutati gli esiti a 3 mesi (mortalità e mRS) tramite visita programmata a 90 giorni all’Ambulatorio Cerebrovascolare o in mancanza di questa tramite follow-up telefonico.

I pazienti trattati con trombolisi endovenosa verrano inseriti nel registro SITS-ISTR (xxx.xxxxxxxxxxxxxxxxx.xxx/)

I pazienti trattati con trombolisi intrarteriosa verranno inseriti contestualmente sia nel registro SITS- ISTR (minimum data set) che nel registro endovascolare italiano. (xxx.xxxxxxxxxxxxxxxxxxxxx.xx)

GESTIONE DELLE COMPLICANZE

EMORRAGIE IN PAZIENTI SOTTOPOSTI A TERAPIA TROMBOLITICA (EV.-

IA): vedi procedura gestione emorragie.

EDEMA MALIGNO ICTUS ISCHEMICO DELL’ARTERIA CEREBRALE

MEDIA: vedi procedura craniectomia decompressiva.

COMPLICANZE IN CORSO DI TERAPIA INTRA-ARTERIOSA:

sanguinamento/aneurisma in sede di introduttore:

- in caso di abbondante sanguinamento, anemizzazione modifica dei parametri vitali. Infondere sangue 2 sacche (disponibilità in PS di gruppo O negativo per trasfusioni urgenti) e nel frattempo richiedere altre sacche.

-Contattare il chirurgo vascolare per valutazione urgente.

-in caso di modifiche dei parametri vitali, trasferimento del paziente in Neurorianimazione.

Document Metadata

Table of Contents

INDICE

Document Metadata