INDICE - Azienda USL di Modena

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Protocollo Ictus - trattamento
trombolitico
U.O. Neurologia NOCSAE
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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 Federica Casoni - Stroke Unit Clinica Neurologica
Dr.ssa Milena Cavazzuti - Stroke Unit Clinica Neurologica
Dr.ssa Francesca Falzone - Stroke Unit Clinica Neurologica
Prof. P. Nichelli – Direttore Clinica Neurologica
Dr.ssa Roberta Pentore - Stroke Unit Clinica Neurologica
Dr. Andrea Zini - Stroke Unit Clinica Neurologica
Dr.ssa Marcella Malagoli - U.O. Neuroradiologia
Dr. Federico Menetti - U.O. Neuroradiologia
Dr. Stefano Vallone - U.O. Neuroradiologia
Dr. Luca Verganti - U.O. Neuroradiologia
Dr. Geminiano Bandiera - Dipartimento Emergenza Urgenza
Dr. Marco Barozzi - Dipartimento Emergenza Urgenza
Dr. Giovanni Pinelli - Dipartimento Emergenza Urgenza
Dr. Stefano Baroni - U.O.Neurorianimazione
Dr. Andrea Marudi - U.O.Neurorianimazione
Dr.ssa Miriam Musiani - U.O.Neurorianimazione
Verifica
Approvazione
Direttore Unità Operativa
Direttore Unità Operativa
Prof. Paolo Frigio Nichelli
Prof. Paolo Frigio Nichelli
Emissione
Referente Accreditamento e Data di emissione
Qualità Unità Operativa
22/11/2011
Dr.ssa Roberta Pentore
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MODIFICHE
Rev.
Approvazione
Data
Visto
Pagine
Modificate
0
Tipo - natura della modifica
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. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR,
Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, 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. Meyers 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. Shaltoni HM, Albright 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.
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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 corso studi di comparazione trombolisi endovenosa verso trombolisi
intrarteriosa (fra 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 intraarteriose, 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
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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 posttrattamento 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 intraarteriosa solo nell’ambito di trials clinici e di protocolli locali con inserimento dei dati in registri
(allegato 1).
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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 (Hacke 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
•
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•
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)
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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 (Smith 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.
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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).
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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:
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 SITSISTR 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 (Mishra 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:
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.
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
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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, Tatter SB, O’Gara PT, Nielsen GP, DeSanctis RW. Fatal intracerebral
hemorrhage following thrompolytic therapy of embolic myocardial infarction in
unsuspected infective endocarditis. Clin Cardiol 1994;17(6):340-4
• Hunter AJ, Girard DE. Thrombolytics in infectious endocarditis associated myocardial
infarction. J Emerg Med. 2001;21(4):401–6.
• Junna M, Lin CC, Espinosa RE, Rabinstein AA. Successful intravenous thrombolysis in
ischemic stroke caused by infective endocarditis. Neurocrit Care. 2007;6(2):117-20.
• Georgoulopoulou E., Cavazzuti M., Casoni F., Nichelli P., Casula N., Zini A. Thrombolytic
treatment in two patients with concealed endocarditis (abstract XL congresso SIN 2009).
Neurol Sci 2009;30:S146-7.
• Bhuva P, Kuo SH, Claude hemphill J, Lopez 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 intraarteriosa, secondo le linee guida americane (Mayers 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, Putaala J, Tatlisumak T, Atula S, Artto V, Curtze S, Häppölä O, Lindsberg PJ,
Mustanoja S, Piironen K, Pitkäniemi J, Rantanen K, Sairanen T, Salonen O, Silvennoinen
H, Soinne L, Strbian D, Tiainen M, Kaste M. Off-label thrombolysis is not associated with
poor outcome in patients with stroke. Stroke. 2010 Jul;41(7):1450-8.
• Breuer L, Blinzler C, Huttner HB, Kiphuth IC, Schwab S, Köhrmann 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.
• Guillan M, Alonso-Canovas A, Garcia-Caldentey J, Sanchez-Gonzalez V, HernandezMedrano I, Defelipe-Mimbrera A, Matute MC, Alonso-Arias MA, Alonso de Leciñana M,
Masjuan J. Off-label intravenous thrombolysis in acute stroke. Eur J Neurol. 2012
Mar;19(3):390-4.
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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 extraintracranica 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. Albers 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. Matute MC et al Safety and Outcomes following Thrombolytic Treatment in Stroke Patients
Who Had Received Prior Treatment with Anticoagulants. Cerebrovasc Dis 2012; 33: 231239.
3. Meyers 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.
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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. Georg Leonhardt et al, Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 21(3),
271–276, 2006.
2. De Keyser 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 (streptokinasiurokinasi e rt-PA). Su 29 trattate, 2 hanno richiesto trasfusione.
Usare con cautela, avvertire la paziente e predisporre per trasfusione.
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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)
trombolisi ev
• 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)
per trombolisi ev
• Informazione del paziente e dei famigliari sui rischi e benefici della terapia off-label
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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:
• 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
• NIHSS 4-24
• Se TAO con INR <1.6
• Glicemia <200 mg/dl
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).
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In caso di ictus con NIHSS>14 o comunque clinicamente classificabili come TACI alla
classificazione OCSP di Bamford è indicato eseguire in urgenza all’arrivo in PS, contestualmente
alla TC encefalo basale, negativa per emorragia, anche :
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)
per trombolisi ev
2° scelta
Criteri di inclusione per trombolisi IA
• 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)
• Valutazione alla AngioTC TSA di accesso anatomico possibile (alla luce delle frequenti
tortuosità dei vasi dell’anziano).
trombolisi ev
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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.
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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:
• NIHSS<17
• Glicemia basale <200 mg/dl
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:
• 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
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ALLEGATI
Allegato 1 KAROLINSKA STROKE UPDATE 2010
Allegato 2 Procedura Applicativa
Allegato 3 Valutazione degli esiti
Allegato 4 gestione delle complicanze
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Protocollo Ictus - trattamento trombolitico
Allegato 2
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 www.eso-stroke.org
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 Peter Ringleb,
Heidelberg, and the session secretary Dr Magnus Thorén, 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 Peter Schellinger, 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.
1
Allegato 2
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).
2
Allegato 2
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.
Meyers PM, Schumacher HC, Higashida RT, Barnwell SL, Creager MA, Gupta R,
McDougall CG, Pandey DK, Sacks D, Wechsler LR. 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.
Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS, Lutsep HL, Rymer
MM, Higashida RT, Starkman S, Gobin YP, Frei D, Grobelny T, Hellinger F, Huddle D, Kidwell C,
Koroshetz W, Marks M, Nesbit G, Silverman IE. Mechanical thrombectomy for acute ischemic
stroke: final results of the Multi MERCI trial. Stroke. 2008;39:1205-1212
4.
Mahon BR, Nesbit GM, Barnwell SL, Clark W, Marotta TR, Weill A, Teal 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, Henkes H, Alfke K, Reith W, Mayer TE, Berlis A, Branca 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, Hiller M, Brekenfeld C, Schroth G, Fischer U, Slotboom J, Arnold M, Gralla
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.
Roth C, Papanagiotou P, Behnke S, Walter S, Haass A, Becker C, Fassbender K, Politi M,
Korner H, Romann MS, Reith W. Stent-Assisted Mechanical Recanalization for Treatment of Acute
Intracerebral Artery Occlusions. Stroke. 2010
8.
Castano C, Dorado L, Guerrero C, Millan M, Gomis M, Perez de la Ossa N, Castellanos
M, Garcia MR, Domenech S, Davalos A. Mechanical thrombectomy with the Solitaire AB device in
large artery occlusions of the anterior circulation: a pilot study. Stroke. 2010;41:1836-1840
3
Allegato 2
9.
Stead LG, Gilmore RM, Bellolio MF, Rabinstein AA, Decker WW. Percutaneous clot
removal devices in acute ischemic stroke: a systematic review and meta-analysis. Arch Neurol.
2008;65:1024-1030
10.
Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a metaanalysis. Stroke. 2007;38:967-973
11.
Brekenfeld C, Schroth G, El-Koussy M, Nedeltchev K, Reinert M, Slotboom J, Gralla 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.
Khatri P, Hill MD, Palesch YY, Spilker J, Jauch EC, Carrozzella JA, Demchuk AM,
Martin R, Mauldin P, Dillon C, Ryckborst KJ, Janis S, Tomsick TA, Broderick JP. Methodology of
the Interventional Management of Stroke III Trial. Int J Stroke. 2008;3:130-137
13.
Pfefferkorn T, Holtmannspotter M, Schmidt C, Bender A, Pfister HW, Straube A, Mayer
TE, Bruckmann H, Dichgans M, Fesl G. Drip, ship, and retrieve: cooperative recanalization therapy
in acute basilar artery occlusion. Stroke. 2010;41:722-726
14.
Molina CA, Selim 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, Lin R, Hussain MS, Jovin TG, Levy EI, Liebeskind DS, Yoo AJ, Hsu DP,
Rymer MM, Tayal AH, Zaidat OO, Natarajan SK, Nogueira RG, Nanda A, Tian M, Hao Q, Kalia
JS, Nguyen TN, Chen M, Gupta R. Conscious 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.
Jumaa MA, Zhang F, Ruiz-Ares G, Gelzinis T, Malik AM, Aleu A, Oakley JI, Jankowitz
B, Lin R, Reddy V, Zaidi SF, Hammer MD, Wechsler LR, Horowitz M, Jovin 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].
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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.
Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical
embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005;36:1432-8.
2.
Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic
stroke: final results of the Multi MERCI trial. Stroke 2008;39:1205-12.
3.
Mahon BR, Nesbit 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, Henkes H, Alfke 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, Hiller M, Brekenfeld 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.
Roth C, Papanagiotou P, Behnke S, et al. Stent-Assisted Mechanical Recanalization
for Treatment of Acute Intracerebral Artery Occlusions. Stroke 2010.
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7.
Castano C, Dorado L, Guerrero C, et al. Mechanical thrombectomy with the Solitaire
AB device in large artery occlusions of the anterior circulation: a pilot study. Stroke 2010;41:183640.
8.
Stead LG, Gilmore RM, Bellolio MF, Rabinstein AA, Decker WW. Percutaneous clot
removal devices in acute ischemic stroke: a systematic review and meta-analysis. Arch Neurol
2008;65:1024-30.
9.
Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a metaanalysis. Stroke 2007;38:967-73.
10.
Khatri P, Hill MD, Palesch YY, et al. Methodology of the Interventional Management
of Stroke III Trial. Int J Stroke 2008;3:130-7.
11.
Molina CA, Selim MH. General or Local Anesthesia During Endovascular
Procedures. Sailing Quiet in the Darkness or Fast Under a Daylight Storm. Stroke 2010.
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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 www.eso-stroke.org
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 Markku Kaste,
Helsinki, Finland, and the session secretary Dr. Nikolaos Kostulas, 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 Risto O. Roine, Turku, Finland, Professor Kennedy R.
Lees, Glasgow, UK, Professor Jan Sobesky, Berlin, Germany, Dr. Michael Mazya, 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 OTT
(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].
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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.
ECASS III 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 Rankin
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, Barthel 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%
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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].
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, 0.841.03)[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 ECASS III 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
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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].
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
≤ 3 hrs
3 – 4.5
hrs
SICH
according to
SITS-MOST
SICH
according to
ECASS II
SICH
according to
NINDS
Mortality 3
months
183/11681
(1.6%)
14/649
(2.2%)
553/11505
(4.8%)
34/636
(5.3%)
846/11646
(7.3%)
52/647
(8.0%)
1263/10368
(12.2%)
70/551
(12.7%)
Mortality 7
days
751/11621
(6.5%)
49/650
(7.5%)
mRS 0-2
5756/10231
(56.3%)
314/541
(58.0%)
mRS 0-1
4084/10231
(39.9%)
219/541
(40.5%)
OR
(95%
CI)
1.32
(1.001.75)
N.A.
2010 analysis
≤ 3 hrs
3 – 4.5 hrs OR
(95% CI)
352/ 21204
(1.7%)
1020/21206
(4.8%)
1.13
(0.971.32)
1.15
(1.00-133)
N.A.
1515/21245
(7.1%)
0.93
(0.841.03)
N.A.
10531/18317
(57.5%)
2287/18583
(12.3%)
1307/20956
(6.2%)
7467/18 317
(40.8%)
52/2317
(2.2%)
1.44
(1.051.97)
121/2304 1.27
(5.3%)
(1.031.55)
171/ 2317 1.18
(7.4%)
(0.991.41)
218/1817 1.26
(12.0%)
(1.071.49.)
132/ 2259 1.22
(5.8%)
(1.001.48)
1075/ 1784 0.84
(60.3%)
(0.750.95)
793/1784 0.92
(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
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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:
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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 SITSISTR 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
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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[2123], 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.
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.
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Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler
JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W; ECASS, ATLANTIS, NINDS and
EPITHET rt-PA Study Group, Allen K, Mau J, Meier D, del Zoppo G, De Silva DA, Butcher KS,
Parsons MW, Barber PA, Levi C, Bladin C, Byrnes 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.
Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M,
Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR,
Patel S, Tilley BC, Albers G: Association of outcome with early stroke treatment: pooled analysis
of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-74.
Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, Barber PA, Bladin C, De
Silva DA, Byrnes G, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G,
Muir K, Gerraty R, Tress BM, Desmond PM; EPITHET investigators. Effects of alteplase beyond 3
h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebocontrolled randomised trial. Lancet Neurol 2008;7:299-309.
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Allegato 2
Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri
Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, for the ECASS Investigators.
Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New Engl J Med
2008;359:1317-29.
Wahlgren N, Ahmed N, Dávalos A, Hacke W, Millán M, Muir K, Roine RO, Toni D, Lees KR.
Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational
study. Lancet 2008;372:1303-9.
Ahmed N, Wahlgren N, Grond M, Hennerici M, Lees KR, Mikulik R, Parsons M, Roine RO, Toni
D, Ringleb 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, Soinne L, Sairanen T, Häppölä O, Lindsberg 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.
Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin 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):50817.
Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, Kaste M, Lipka LJ, Pedraza S,
Ringleb PA, Rowley HA, Schneider D, Schwamm LH, Leal JS, Söhngen M, Teal PA, WilhelmOgunbiyi K, Wintermark 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.
Mishra NK, Albers GW, Davis SM, Donnan GA, Furlan AJ, Hacke W, Lees KR. Mismatch-based
delayed thrombolysis: a meta-analysis. Stroke 2010;41:e25-33. Erratum in: Stroke 2010;41:e399.
Zaro-Weber O, Moeller-Hartmann W, Heiss WD, Sobesky J. MRI perfusion maps in acute stroke
validated with 15O-water positron emission tomography. Stroke. 2010 Mar;41(3):443-9. Epub 2010
Jan 14.
Sobesky J, Zaro Weber O, Lehnhardt FG, Hesselmann V, Neveling M, Jacobs A, Heiss WD. Does
the mismatch match the penumbra? Magnetic resonance imaging and positron emission tomography
in early ischemic stroke. Stroke 2005;36:980-5.
Kakuda W, Lansberg MG, Thijs VN, Kemp SM, Bammer R, Wechsler LR, et al. Optimal definition
for PWI/DWI mismatch in acute ischemic stroke patients. J Cereb Blood Flow Metab 2008;28:88791.
Campbell BC, Christensen S, Foster SJ, Desmond PM, Parsons MW, Butcher KS,Barber PA, Levi
CR, Bladin CF, Donnan GA, Davis SM; EPITHET Investigators. Visual assessment of perfusiondiffusion mismatch is inadequate to select patients for thrombolysis. Cerebrovasc Dis.
2010;29(6):592-6. Epub 2010 Apr 14. PubMed PMID: 20389068.
Kranz PG, Eastwood 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. Campbell 2010)
Schaefer PW, Barak ER, Kamalian S, Gharai LR, Schwamm L, Gonzalez RG, Lev 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.
Thomalla G, Rossbach P, Rosenkranz M, Siemonsen S, Krützelmann A, Fiehler J, Gerloff C.
Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or
less. Ann Neurol 2009;65:724-32.
Mishra NK, Ahmed N, Andersen G, Egido JA, Lindsberg PJ, Ringleb PA, Wahlgren 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)
14
Allegato 2
Mishra NK, Davis SM, Kaste M, Lees KR 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)
Mateen FJ, Buchan AM, Hill MD; CASES Investigators. Outcomes of thrombolysis for acute
ischemic stroke in octogenarians versus nonagenarians. Stroke 2010;41:1833-5.
Alshekhlee A, Mohammadi A, Mehta S, Edgell RC, Vora N, Feen E, Kale S, Shakir ZA, CruzFlores S. Is thrombolysis safe in the elderly?: analysis of a national database. Stroke 2010;41:225964.
Longstreth WT Jr, Katz R, Tirschwell DL, Cushman M, Psaty BM. Intravenous tissue plasminogen
activator and stroke in the elderly. Am J Emerg Med 2010;28:359-63.
Khatri P, Kleindorfer DO, Yeatts SD, Saver JL, Levine SR, Lyden PD, Moomaw CJ, Palesch YY,
Jauch EC, Broderick JP. Strokes with minor symptoms: an exploratory analysis of the National
Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator trials.
Stroke 2010;41:2581Meretoja A, Putaala J, Tatlisumak T, Atula S, Artto V, Curtze S, Häppölä O, Lindsberg PJ,
Mustanoja S, Piironen K, Pitkäniemi J, Rantanen K, Sairanen T, Salonen O, Silvennoinen H,
Soinne L, Strbian D, Tiainen M, Kaste M. Off-label thrombolysis is not associated with poor
outcome in patients with stroke. Stroke 2010;41:1450-8.
Mishra NK, Diener HC, Lyden PD, Bluhmki E, Lees KR; 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)
Ford GA, Ahmed N, Azevedo E, Grond M, Larrue V, Lindsberg PJ, Toni D, Wahlgren N.
Intravenous alteplase for stroke in those older than 80 years old. Stroke 2010 ;41:2568-74.
15
Allegato 2
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:
16
Allegato 2
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
17
Allegato 2
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[1719], 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.
found similar benefit as in patients without stroke or diabetes [24,25].
NEW REFERENCES:
Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri
Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, for the ECASS Investigators.
Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New Engl J Med
2008;359:1317-29.
Wahlgren N, Ahmed N, Dávalos A, Hacke W, Millán M, Muir K, Roine RO, Toni D, Lees KR.
Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational
study. Lancet 2008;372:1303-9.
Ahmed N, Wahlgren N, Grond M, Hennerici M, Lees KR, Mikulik R, Parsons M, Roine RO, Toni
D, Ringleb 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, Soinne L, Sairanen T, Häppölä O, Lindsberg 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.
Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler
JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W; ECASS, ATLANTIS, NINDS and
EPITHET rt-PA Study Group, Allen K, Mau J, Meier D, del Zoppo G, De Silva DA, Butcher KS,
Parsons MW, Barber PA, Levi C, Bladin C, Byrnes 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.
Thomalla G, Rossbach P, Rosenkranz M, Siemonsen S, Krützelmann A, Fiehler J, Gerloff C.
Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or
less. Ann Neurol 2009;65:724-32.
Campbell BC, Christensen S, Butcher KS, Gordon I, Parsons MW, Desmond PM, Barber PA, Levi
CR, Bladin CF, De Silva DA, Donnan GA, Davis 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;41:828.
Zaro-Weber O, Moeller-Hartmann W, Heiss WD, Sobesky 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.
18
Allegato 2
Sobesky J, Zaro Weber O, Lehnhardt FG, Hesselmann V, Neveling M, Jacobs A, Heiss WD. Does
the mismatch match the penumbra? Magnetic resonance imaging and positron emission tomography
in early ischemic stroke. Stroke 2005;36:980-5.
Kakuda W, Lansberg MG, Thijs VN, Kemp SM, Bammer R, Wechsler LR, et al. Optimal definition
for PWI/DWI mismatch in acute ischemic stroke patients. J Cereb Blood Flow Metab 2008;28:88791.
Kranz PG, Eastwood 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. Campbell 2010)
Schaefer PW, Barak ER, Kamalian S, Gharai LR, Schwamm L, Gonzalez RG, Lev 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.
Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, Barber PA, Bladin C, De
Silva DA, Byrnes G, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G,
Muir K, Gerraty R, Tress BM, Desmond PM; EPITHET investigators. Effects of alteplase beyond 3
h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebocontrolled randomised trial. Lancet Neurol 2008;7:299-309.
Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, et al. Magnetic resonance
evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. 2006 Nov;60(5):50817.
Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, Kaste M, Lipka LJ, Pedraza S,
Ringleb PA, Rowley HA, Schneider D, Schwamm LH, Leal JS, Söhngen M, Teal PA, WilhelmOgunbiyi K, Wintermark 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.
Mishra NK, Albers GW, Davis SM, Donnan GA, Furlan AJ, Hacke W, Lees KR. Mismatch-based
delayed thrombolysis: a meta-analysis. Stroke 2010;41:e25-33. Erratum in: Stroke 2010;41:e399.
Alshekhlee A, Mohammadi A, Mehta S, Edgell RC, Vora N, Feen E, Kale S, Shakir ZA, CruzFlores S. Is thrombolysis safe in the elderly?: analysis of a national database. Stroke 2010;41:225964.
Longstreth WT Jr, Katz R, Tirschwell DL, Cushman M, Psaty BM. Intravenous tissue plasminogen
activator and stroke in the elderly. Am J Emerg Med 2010;28:359-63.
Khatri P, Kleindorfer DO, Yeatts SD, Saver JL, Levine SR, Lyden PD, Moomaw CJ, Palesch YY,
Jauch EC, Broderick JP. Strokes with minor symptoms: an exploratory analysis of the National
Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator trials.
Stroke 2010;41:2581-6.
Mateen FJ, Buchan AM, Hill MD; CASES Investigators. Outcomes of thrombolysis for acute
ischemic stroke in octogenarians versus nonagenarians. Stroke 2010;41:1833-5.
Mishra NK, Diener HC, Lyden PD, Bluhmki E, Lees KR; 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)
Mishra NK, Ahmed N, Andersen G, Egido JA, Lindsberg PJ, Ringleb PA, Wahlgren 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)
Ford GA, Ahmed N, Azevedo E, Grond M, Larrue V, Lindsberg PJ, Toni D, Wahlgren N.
Intravenous alteplase for stroke in those older than 80 years old. Stroke 2010 ;41:2568-74.
19
Allegato 2
Mishra NK, Davis SM, Kaste M, Lees KR 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)
Meretoja A, Putaala J, Tatlisumak T, Atula S, Artto V, Curtze S, Häppölä O, Lindsberg PJ,
Mustanoja S, Piironen K, Pitkäniemi J, Rantanen K, Sairanen T, Salonen O, Silvennoinen H,
Soinne L, Strbian D, Tiainen M, Kaste M. Off-label thrombolysis is not associated with poor
outcome in patients with stroke. Stroke 2010;41:1450-8.
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. Chalela J, Kidwell C, Nentwich L, Luby M, Butmann J, Demchuk A, Hill M, Patronas N,
Latour L, Warach S: Magnetic resonance imaging and computed tomography in emergency
assessment of patients with suspected acute stroke: a prospective comparison. Lancet
2007;369:293-298.
28. Kane I, Sandercock P, Wardlaw 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. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, Bammer R, Kakuda W,
Lansberg MG, Shuaib A, Coplin W, Hamilton S, Moseley M, Marks MP: Magnetic resonance
evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508-517.
30. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E,
Davis S, Donnan G, Scheider D, Diez-Tejedor E, Trouilas P: Randomised double-blind placebocontrolled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke
(ECASS II). Lancet 1998;352:1245-1251
31. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E,
Höxter G, Mahagne MH, Hennerici M: Intravenous thrombolysis with recombinant tissue
plasminogen activator for acute stroke. JAMA 1995;274:1017-1025.
32. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M,
Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR,
Patel S, Tilley BC, Albers G: Association of outcome with early stroke treatment: pooled analysis
of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774
33. Sylaja PN, Cote R, Buchan AM, Hill 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. van Oostenbrugge RJ, Hupperts RM, Lodder 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. Ringleb PA, Schwark C, Köhrmann M, Külkens S, Jüttler E, Hacke W, Schellinger 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. Hill MD, Buchan AM: Thrombolysis for acute ischemic stroke: results of the Canadian
Alteplase for Stroke Effectiveness Study (CASES). CMAJ 2005;172:1307-1312.
37. Bateman BT, Schumacher HC, Boden-Albala B, Berman MF, Mohr JP, Sacco RL, PileSpellman 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. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M,
Külkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G: Thrombolysis with
20
Allegato 2
alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMonitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282.
39. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM: Quality improvement and
tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke
2003;34:799-800.
40. Graham GD: Tissue plasminogen activator for acute ischemic stroke in clinical practice: a metaanalysis of safety data. Stroke 2003;34:2847-2850
41. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J,
Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW: Ultrasound-enhanced systemic
thrombolysis for acute ischemic stroke. N Engl J Med 2004;351:2170-2178.
42. Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, Arenillas JF,
Huertas R, Purroy F, Delgado P, Alvarez-Sabin 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. Köhrmann M, Jüttler E, Fiebach JB, Huttner HB, Siebert S, Schwark C, Ringleb PA,
Schellinger PD, Hacke 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. Schellinger PD, Thomalla G, Fiehler J, Kohrmann M, Molina CA, Neumann-Haefelin T, Ribo
M, Singer OC, Zaro-Weber O, Sobesky 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. Lansberg MG, Thijs VN, Bammer R, Kemp S, Wijman CA, Marks MP, Albers GW: Risk
factors of symptomatic intracerebral hemorrhage after tPA therapy for acute stroke. Stroke
2007;38:2275-2278
21
Allegato 2
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.
Allegato 3
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
(www.sitsinternational.org/)
I pazienti trattati con trombolisi intrarteriosa verranno inseriti contestualmente sia nel registro SITSISTR (minimum data set) che nel registro endovascolare italiano.
(www.registroendovascolare.it)
Allegato 4
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.

INDICE - Azienda USL di Modena

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