5. Traitement de l’AVC ischémique aigu

Les méta-analyses des essais cliniques randomisés portant sur l’administration d’altéplase par voie intraveineuse pour traiter l’AVC ischémique aigu révèlent que le traitement thrombolytique peut réduire le risque d’incapacités et de décès, malgré le faible risque d’hémorragie grave. Le dernier moment après l’apparition de l’AVC auquel il est encore opportun d’administrer l’altéplase n’est pas encore défini avec précision. Toutefois, les données actuelles indiquent que son administration produit des effets bénéfiques jusqu’à 4,5 heures après l’apparition des symptômes. Une forte relation inversement proportionnelle demeure cependant entre le retard du traitement et les résultats cliniques. Les patients admissibles doivent donc être traités le plus tôt possible.

La thrombectomie endovasculaire s’est avérée réduire les taux d’incapacité et de mortalité associés à l’AVC ischémique aigu. Initialement, la thrombectomie endovasculaire était réservée aux personnes présentant une occlusion de gros vaisseaux liés à la circulation antérieure ou un noyau ischémique de petite taille (note ≥ 6 à l’échelle ASPECTS), ou aux personnes ayant subi un AVC relativement invalidant. De plus, l’intervention devait avoir lieu rapidement (généralement dans les 6 heures suivant l’apparition des symptômes). On a signalé un nombre de sujets à traiter aussi bas que 2,6 (3) pour réduire le taux d’incapacité d’au moins 1 point à l’échelle de Rankin modifiée à 90 jours (Goyal et al. 2016). Plus récemment, les critères d’admissibilité à la thrombectomie endovasculaire ont été revus afin d’inclure les personnes chez qui les symptômes d’AVC se manifestent plus tardivement, celles ayant subi un AVC léger ou un infarctus de la circulation postérieure, et celles présentant un noyau ischémique de grande taille (note de 2 à 5 à l’échelle ASPECTS). Ainsi, un plus grand nombre peut tirer profit de ce traitement qui sauve des vies.

Les personnes ayant une expérience vécue ont insisté sur l’importance de discuter de la situation avec ses proches avant un changement dans l’état de santé. Autrement, il peut être difficile de connaître les souhaits de la personne. Certaines personnes ont admis que ces conversations, même celles portant sur le désir de participer à un essai clinique ou de recevoir un traitement expérimental, peuvent s’avérer utiles avant un changement de l’état de santé. De même, les personnes ayant une expérience vécue ont rappelé l’importance de faire part de ses valeurs et préférences personnelles à son équipe de soins afin d’orienter les décisions relatives aux traitements.

(Remarque : Critères de l’essai DAWN, score de Rankin modifié de 0 à 2 à 90 jours [49 % contre 13 % = NST de 2,8]; méta-analyse de l’essai HERMES de 2016 pour obtenir le score de Rankin modifié de 0 à 2 à 90 jours [46 % contre 26,5 % = NST de 5,1]).

Pour s’assurer que les personnes qui subissent un AVC sont évaluées, prises en charge et traitées rapidement, les équipes interdisciplinaires doivent avoir accès à l’infrastructure et aux ressources nécessaires. Les exigences peuvent comprendre les éléments ci-dessous, qui sont établis à l’échelle des systèmes.

1. Des protocoles locaux doivent prioriser les patients qui ont subi un AVC afin de leur accorder un accès immédiat au diagnostic approprié, y compris à la TDM et à l’imagerie neurovasculaire avec angiographie par TDM. Cette approche doit concerner aussi bien les patients dont on connaît le moment de l’apparition des symptômes (ou le dernier moment auquel ils ont été vus en bonne santé) que ceux chez qui les symptômes ont été remarqués au réveil. 
2. Des systèmes de soins coordonnés et intégrés auxquels participent tout le personnel pertinent pour les soins en milieu préhospitalier et au service des urgences, y compris le personnel paramédical, le personnel du service des urgences, les équipes de prise en charge de l’AVC, les radiologues et les neuro-interventionnistes, doivent être mis en place pour les patients ayant subi un AVC. Des protocoles doivent avoir été mis en place en partenariat avec les agences de SMU et les hôpitaux traitants, ainsi qu’entre les hôpitaux des systèmes de soins de l’AVC en vue de garantir un transport rapide aux centres fournissant des services avancés de l’AVC pour respecter la fenêtre temporelle du traitement.
3. Il convient de tenir compte des résidents des régions nordiques, rurales et éloignées ainsi que des Autochtones pour garantir un accès immédiat aux diagnostics appropriés et un traitement en temps opportun.
4. (NOUVEAUTÉ EN 2022) Les dirigeants des systèmes de santé doivent collaborer avec les hôpitaux pour coordonner les plans de lancement du traitement par ténectéplase et envisager l’achat groupé. Santé Canada doit entreprendre un examen et une approbation rapides de la ténectéplase pour traiter l’AVC en phase aiguë.
5. Les régions sanitaires et les systèmes de traitement de l’AVC doivent examiner l’agrandissement de la fenêtre temporelle de traitement par thrombectomie endovasculaire (jusqu’à 24 heures dans certains cas rigoureusement sélectionnés) et déterminer les possibles répercussions sur les ressources. La demande en imagerie augmentera, surtout dans les centres de soins complets et ceux offrant la thrombectomie endovasculaire. Il faut tenir compte de la dotation en personnel, des heures de service et de la capacité afin d’assurer l’efficience et l’efficacité des services offerts. 
6. Les planificateurs du système et les spécialistes du roulement des patients doivent prendre des mesures en prévision des difficultés considérables qui risquent de découler du transfert des possibles candidats à la thrombectomie endovasculaire vers les centres offrant cette intervention. Le changement aura des répercussions sur les services des urgences, les services de radiologie et les unités d’hospitalisation de soins de courte durée, où le taux d’occupation est trop élevé (de plus de 100 % dans bien des établissements).
7. Le savoir-faire en neurologie et en neuro-intervention de l’AVC doit être régionalisé et un système doit être mis en place à l’échelle des régions en vue de permettre un accès rapide aux médecins chevronnés en traitement thrombolytique en phase aiguë et en traitements endovasculaires, y compris par l’entremise de la télémédecine. Il doit notamment y avoir des protocoles sur la communication avec les médecins possédant des connaissances spécialisées en AVC pour la thrombolyse intraveineuse, ainsi que sur le transport vers des centres de soins de l’AVC plus avancés, au besoin, pour l’administration de traitements d’urgence. 
8. Les régions sanitaires et les établissements universitaires doivent renforcer les capacités des neuro-interventionnistes dûment formés afin de pouvoir compter sur un nombre suffisant de professionnels pour répondre aux besoins régionaux et provinciaux en thrombectomie endovasculaire.
9. Des protocoles d’urgence pour le traitement en phase aiguë doivent être mis en place et bien communiqués à l’ensemble des professionnels de la santé de l’hôpital relativement à la prise en charge des personnes hospitalisées qui ont subi un AVC pour assurer l’accès à la TDM cérébrale ainsi qu’à l’angiographie par TDM des vaisseaux extra-crâniens et intracrâniens dès que possible après l’apparition des symptômes.
10. L’ensemble des patientes et patients doivent avoir accès à des unités spécialisées de prise en charge de l’AVC en phase aiguë, dont le personnel possède de l’expérience dans la prise en charge des personnes traitées par thrombolyse intraveineuse ou thrombectomie endovasculaire.
11. Les programmes d’intervention endovasculaire évoluent partout au Canada; les décisions relatives au site pertinent, aux protocoles de transfert et de contournement, et aux échéances seront prises à l’échelle provinciale ou régionale. Les décisions relatives au moment où ces services sont dits pleinement opérationnels et aux patients devant être transférés en ambulance à ces établissements doivent être prises à l’échelle provinciale ou régionale, et communiquées à tous les intervenants pertinents.
12. Des tomodensitomètres hélicoïdaux adéquatement programmés pour l’angiographie par TDM (multiphase ou dynamique) et les séquences de perfusion par TDM doivent être disponibles, ainsi que des logiciels de post-traitement adéquats optimisés pour la production d’images de qualité élevée.
13. Il convient de surveiller l’accès, les résultats et les principaux processus de soins assurant la rapidité d’intervention.
14. La capacité des hôpitaux offrant la thrombectomie endovasculaire doit être maintenue alors que la demande pour ce traitement augmente (il faut donc assurer la responsabilisation de l’ensemble des professionnels de la santé accédant à ces services ou les offrant, veiller à ce que le financement tienne le rythme et garantir l’accès à des soins sûrs et opportuns).

Indicateurs du système :

1. Proportion de patients de communautés rurales ou éloignées recevant une thrombolyse intraveineuse par l’entremise de la technologie de Télé-AVC (par rapport à tous les patients ayant subi un AVC ischémique dans ces communautés et par rapport à toutes les consultations par Télé-AVC pour un AVC ischémique).

Indicateurs de processus :

2. Proportion globale de patients ayant subi un AVC ischémique et ayant reçu une thrombolyse intraveineuse (prioritaire).
3. Temps médian écoulé (en minutes) entre l’arrivée du patient au service des urgences et la thrombolyse intraveineuse.
4. Proportion de patients ayant subi un AVC ischémique et ayant reçu une thrombolyse intraveineuse dans les 3 à 4,5 heures suivant l’apparition des symptômes.
5. Proportion de patients ayant subi un AVC ischémique et ayant reçu une thrombolyse dans les 30 minutes suivant leur arrivée à l’hôpital (prioritaire).
6. Proportion de patients ayant subi un AVC ischémique et ayant été traités par thrombectomie endovasculaire (prioritaire).
7. Temps médian écoulé entre l’arrivée à l’hôpital et la ponction artérielle, et entre la TDM (première tranche de la TDM sans injection de produit de contraste) et la ponction artérielle chez les patients faisant l’objet d’une thrombectomie endovasculaire. 
8. Temps médian écoulé entre l’arrivée à l’hôpital et la première reperfusion pour les patients faisant l’objet d’une thrombectomie endovasculaire. Le moment de la première reperfusion correspond à la première image d’angiographie illustrant un rétablissement partiel ou total de la perfusion du territoire artériel touché (Projet spécial sur l’AVC 440 de l’ICIS. Voir la note relative à la mesure des indicateurs ii. ci-dessous.)
9. Proportion de patients ayant subi un AVC et ayant reçu une thrombolyse intraveineuse et une thrombectomie endovasculaire.
10. Pour les patients qui ont fait un AVC alors qu’ils étaient hospitalisés pour d’autres raisons médicales, temps médian écoulé entre la dernière fois où le patient a été vu en bonne santé et l’imagerie cérébrale. 
11. Pour les patients qui ont fait un AVC alors qu’ils étaient hospitalisés pour d’autres raisons médicales, temps médian écoulé entre la dernière fois où le patient a été vu en bonne santé et la thrombolyse ou la thrombectomie endovasculaire (ponction artérielle) en phase aiguë.
12. Pour les patients recevant un traitement de reperfusion endovasculaire, reperfusion finale quantifiée à l’aide du système Modified Thrombolysis in Cerebral Infarction (mTICI). (Projet spécial sur l’AVC 440 de l’ICIS. Voir la note relative à la mesure des indicateurs ii. ci-dessous.)
13. Proportion de patients présentant une hémorragie sous-arachnoïdienne ou intracérébrale symptomatique après une thrombolyse intraveineuse ou une thrombectomie endovasculaire, soit tout cas d’hématome parenchymateux de 1er ou de 2e degré (PH1 ou PH2), d’hémorragie intracrânienne distale (RIH), d’hémorragie sous-arachnoïdienne (SAH) ou d’hémorragie intraventriculaire (IVH) associé à une perte d’au moins quatre points au score NIHSS en moins de 24 heures.
14. Soins virtuels de l’AVC – proportion de patients ayant subi un AVC en phase aiguë et ayant eu une consultation virtuelle avec un spécialiste de l’AVC d’un autre milieu de soins, ce qui a mené à une thrombolyse en phase aiguë.
15. Soins virtuels de l’AVC – proportion de patients ayant subi un AVC pris en charge par Télé-AVC qui ont reçu l’activateur du plasminogène tissulaire (tPA), qui ont souffert d’une HI secondaire symptomatique ou d’une hémorragie systémique, qui sont décédés à l’hôpital ou qui ont obtenu leur congé de l’hôpital et été orientés vers un établissement de soins de longue durée, plutôt que de retourner à la maison ou d’être dirigés vers un centre de réadaptation.

Indicateurs de résultats et d’expérience axés sur le patient :

16. Degré de déficit fonctionnel à la suite d’un AVC en phase aiguë; capacité à accomplir les activités de la vie quotidienne de façon autonome.
17. Score de Rankin modifié de tous les patients ayant subi un AVC qui reçoivent une thrombolyse intraveineuse ou une thrombectomie endovasculaire le 30e jour et le 90e jour après avoir reçu le congé de l’hôpital.
18. Proportion de patients présentant une hémorragie sous-arachnoïdienne ou intracérébrale symptomatique après une thrombectomie endovasculaire, soit tout cas d’hématome parenchymateux de 1er ou de 2e degré (PH1 ou PH2), d’hémorragie intracrânienne distale (RIH), d’hémorragie sous-arachnoïdienne (SAH) ou d’hémorragie intraventriculaire (IVH) associé à une perte d’au moins quatre points au score NIHSS en moins de 24 heures.
19. Taux de mortalité à l’hôpital (global et dans les 30 jours) pour les patients ayant subi un AVC ischémique, catégorisé en fonction de l’administration ou non d’une thrombolyse intraveineuse ou d’une thrombectomie endovasculaire.

Notes relatives à la mesure des indicateurs

1. Voir le document sur les indicateurs de qualité clés pour les soins de l’AVC au Canada et les définitions de cas d’AVC (7^e édition) pour connaître les calculs, l’échéancier des processus et les mesures des résultats liés à la thrombolyse intraveineuse et à la thrombectomie endovasculaire.
2. Le dénominateur des indicateurs de traitement correspond au nombre de personnes ayant reçu leur congé du service des urgences (SNISA de l’ICIS) ou des soins de courte durée (BDCP de l’ICIS) et un diagnostic d’AVC ischémique (voir le dictionnaire de données pour connaître les codes de la Classification statistique internationale des maladies et des problèmes de santé connexes [CIM-10] pertinents).
3. L’ICIS a créé un projet spécial (440) sur la qualité des soins de l’AVC dans le cadre de l’extraction de la BDCP, qui permet la collecte de données concernant six indicateurs de rendement relatifs à la thrombectomie endovasculaire. Il en est question aux indicateurs de rendement 7 et 10 ci-dessus sous le nom de « Projet spécial sur l’AVC 440 de l’ICIS ».
4. Les données peuvent être extraites des dossiers médicaux des patients par examen ou vérification, ou en consultant le registre.
5. Les mesures d’intervalles de temps doivent être calculées à partir du triage du patient à l’hôpital (selon les normes de soins du service des urgences, le triage a lieu avant l’admission; l’heure du triage doit toujours servir à la normalisation) jusqu’à l’heure d’administration de la thrombolyse intraveineuse indiquée dans le dossier du patient (notes de soins infirmiers, dossier du service des urgences ou dossier des médicaments). 
6. Pour ce qui est des indicateurs de rendement liés aux intervalles de temps, il convient de calculer tous les percentiles, puis d’examiner les 50e et 90e percentiles, ainsi que l’intervalle entre les quartiles.
7. Au moment de noter s’il y a eu thrombolyse intraveineuse, il faut inclure l’heure à laquelle l’administration du bolus (d’altéplase et de ténectéplase) a eu lieu et l’heure de début de la perfusion (d’altéplase). Il y a souvent du retard entre l’administration du bolus et celle de la perfusion, ce qui peut réduire l’efficacité de l’altéplase. Il faut aussi préciser la voie d’administration, puisque les seuils de référence temporels pour l’administration par voie intraveineuse et endovasculaire diffèrent.
8. Dans le cas de la thrombectomie endovasculaire, l’heure du traitement correspond au moment où la première ponction artérielle est réalisée.

Les ressources et les outils ci-dessous qui sont externes à Cœur + AVC et aux Recommandations peuvent être utiles à la mise en œuvre des soins de l’AVC. Cependant, leur présence ne constitue pas une approbation réelle ou implicite par le groupe de rédaction des pratiques optimales en matière de soins de l’AVC. Le lecteur est encouragé à examiner ces ressources et ces outils d’un œil critique et à les mettre en œuvre dans sa pratique à sa discrétion.

Renseignements destinés aux dispensateurs de soins

• Tableau 4 de l’annexe 3 du module sur la prise en charge de l’AVC en phase aiguë des Recommandations : « Outils de dépistage et d’évaluation de la gravité de l’AVC »
• Énoncé de consensus sur la prise en charge de l’AVC en phase aiguë pendant la grossesse’ des Recommandations 
• Voir l’encadré 5A : « Critères pour les centres qui offrent le traitement de l’AVC ischémique aigu »
• Voir l’encadré 5B : « Critères pour le traitement thrombolytique aigu avec altéplase par voie intraveineuse » 
• Cœur + AVC, « Trousse d’outils pour la mise en œuvre des soins virtuels de l’AVC » 
• Cœur + AVC, « Agir en vue de soins optimaux communautaires et de longue durée de l’AVC : Une ressource pour les dispensateurs de soins de santé » 
• American College of Chest Physicians (ACCP), lignes directrices sur l’anticoagulation (en anglais seulement)
• ASPECTS (en anglais seulement) 
• Info AVC 
• Cœur + AVC, « Liste de vérification du protocole relatif à la thrombolyse intraveineuse à la suite d’un AVC ischémique aigu »
• Heart & Stroke: 2022 Acute Stroke Management Key Quality Indicators (en anglais seulement)
• Les responsables de la coordination pour les pratiques optimales de soins de l’AVC en phase aiguë (en Ontario) et le Ontario Regional Education Group, en partenariat avec Cœur + AVC : Principaux changements apportés aux recommandations canadiennes pour les pratiques optimales de soins de l’AVC en phase aiguë 2022. (Disponible en anglais seulement)

Renseignements destinés aux personnes ayant une expérience vécue, y compris les membres de la famille, les amis et les aidants

• Cœur + AVC, « Votre cheminement après un AVC » 
• Cœur + AVC, « Liste de vérification après un AVC » 
• Cœur + AVC, « Infographie sur la prise en charge de l’AVC en phase aiguë » 
• Cœur + AVC, « Agir en vue de soins optimaux communautaires et de longue durée de l’AVC : Une ressource pour les dispensateurs de soins de santé »  
• Info AVC 

Evidence Table and Reference List 5 (Acute Ischemic Stroke Treatment – Thrombolytic Therapy)

Evidence Table and Reference List 5b (Acute Ischemic Stroke Treatment – Endovascular Therapy)

Sex and Gender Considerations Reference List

The weight of evidence from many large, international trials over a time frame of 20 years clearly indicate that treatment with intravenous alteplase reduces the risk of death or disability following ischemic stroke, at 3 to 6 months post-treatment. The NINDS trial (1995) was one of the earliest, large trials conducted in the USA. Patients were randomized to receive alteplase or placebo within three hours of symptom onset. At 3 months, significantly more patients in the t-PA group had experienced a good outcome (using any one of the study’s four metrics), with no difference in 90-day mortality between groups. In contrast, patients who received alteplase within 3 to 5 hours in the ATLANTIS trial (1999) were no more likely to have a good neurological or functional outcome at 90 days than patients in the placebo group. 

In the first ECASS trial (1995) 620 patients received alteplase or placebo within 6 hours of the stroke event. Using intention-to-treat analysis and including the data from 109 patients with major protocol violations, the authors did not report a significant benefit of treatment. The median Barthel Index and modified Rankin scores at 90 days did not differ between groups. In an analysis restricted to patients in the target population, there were differences favouring patients in the alteplase group. In the ECASS II trial (1998), there was again no significant difference on any of the primary outcomes. The percentages of patients with a good outcome at day 90 (mRS<2) treated with alteplase and placebo were 40.3% vs. 36.6% respectively, absolute difference=3.7%, p=0.277. In subgroup analysis of patients treated <3 hours and 3 to 6 hours, there were no between-group differences on any of the outcomes. The authors suggested that the reason for the null result may have been that the study was underpowered, since it was powered to detect a 10% difference in the primary outcome, but the observed difference between groups in previous trials was only 8.3%. Finally, in the ECASS III trial (2008) 821 patients were randomized within 3 and 4.5 hours of symptom onset. In this trial, a higher percentage of patients in the alteplase group experienced a favourable outcome, defined as mRS scores <2 (52.4% vs. 45.2%, adjusted OR=1.34, 95% CI 1.02 to 1.76, p=0.04). A higher percentage of patients in the alteplase group also had NIHSS scores of 0 or 1, (50.2% vs. 43.2%, adjusted OR=1.33, 95% CI 1.01 to 1.75, p=0.04). Secondary outcomes of the ECASS III trial were reported by Bluhmki et al. (2009). At 90 days, there were no between-group differences in the percentages of patients with mRS score of 0-2 (59% vs. 53%, p=0.097) or BI score ≥85 (60% vs. 56%, p=0.249, but a significantly greater percentage of patients had improved NIHSS scores of ≥8 points (58% vs. 51%, p=0.031). In all of the trials described above there was an increased risk of symptomatic intracerebral hemorrhage (ICH) associated with treatment with alteplase and in some cases, increased short-term mortality; however, there were no differences between treatment and placebo groups in 90-day mortality. 

The Third International Stroke Trial (IST-3, 2012) is the largest (n=3,035) and most recent trial of alteplase, in which patients were randomized to receive a standard dose of alteplase (0.9 mg/kg) or placebo. Investigators aimed to assess the risks and benefits of treatment among a broader group of patients, and determine if particular subgroups of patients might benefit preferentially from treatment. In this trial, 95% of patients did not meet the strict licensing criteria, due to advanced age or time to treatment. Unlike all previous large trials, which excluded them, IST-3 included patients >80 years of age. In fact, the majority of patients (53%) were >80 years of age. Approximately one-third of all patients were treated within 0-3 hours, 3.0-4.5 hours, and 4.5-6.0 hours of onset of symptoms. Overall, there was an increase in the risk of death within 7 days in patients who had received alteplase, although there was no difference in 6-month mortality in both crude and adjusted analyses. There was no significant difference in the percentage of patients who were treated with alteplase who were alive and independent (defined as an Oxford Handicap Score of 0-1) at 6 months (37% vs. 35%, adjusted OR=1.13, 95% CI 0.95 to 1.35, p=0.181, although a secondary ordinal analysis suggested a significant, favourable shift in the distribution of OHS scores at 6 months. Significantly improved odds of a good outcome at 6 months were associated with the subgroups of older patients (≥80 years), higher NIHSS scores, higher baseline probability of good outcome and treatment within 3 hours. Fatal or non-fatal symptomatic intracranial hemorrhage within 7 days occurred more frequently in patients in the t-PA group (7% vs. 1%, adjusted OR=6.94, 95% CI 4.07 to 11.8, p<0.0001). The 3-year risk of mortality (2016) was similar between groups (47% vs. 47%, 95% CI 3.6%, 95% CI -0.8 to 8.1); however, patients who received rt-PA had a significantly lower risk of death between 8 days and 3 years (41% vs. 47%; HR= 0.78, 95% CI 0·68–0·90, p=0·007).

Although it is known that the optimal timing of administration of intravenous alteplase is <3 hours, debate continues as to the safety and efficacy of treatment provided between 3 and 6 hours post stroke. The results from a few studies suggest that treatment is still beneficial if provided beyond the three-hour window. The Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) includes patients who were treated with intravenous alteplase under strict licensing criteria and also those who were thought to be good candidates based on clinical/imaging assessment of the treating facility. Wahlgren et al. (2008) used data from a cohort of patients collected from 2002–2007 to compare the outcomes of patients who had been treated with alteplase within 3 hours of symptom onset (n=11,865) and those treated within 3 to 4.5 hours (n=644). The primary focus of this analysis was to assess treatment safety beyond the three-hour treatment window. Patients in the <3-hour group had significantly lower initial median NIHSS scores (11 vs. 12, p<0.0001). There were no significant between-group differences on any of the outcomes (symptomatic ICH within 24-36 hours, mortality within 3 months, or percentage of patients who were independent at 3 months); however, there was a trend towards increased number of patients treated from 3 to 4.5 hours who died (12.7% vs. 12.2%, adjusted OR=1.15, 95% CI 1.00-1.33, p=0.053) and who experienced symptomatic ICH (2.2% vs. 1.6%, adjusted OR=1.32, 95% CI 1.00-1.75, p=0.052). Additional analysis from the SITS-ISTR cohort was conducted to further explore the timing of alteplase treatment (Ahmed et al. 2010). In this study, patients treated within 3 hours (n=21,566) and 3 to 4.5 hours (n=2,376) of symptom onset between 2007 and 2010, were again compared. Significantly more patients treated from 3-4.5 hours experienced a symptomatic ICH (2.2% vs.1.7%, adjusted OR=1.44, 95% CI 1.05-1.97, p=0.02), and were dead at 3 months (12.0% vs. 12.3%, adjusted OR=1.26, 95% CI 1.07-1.49, p=0.005). Significantly fewer patients treated from 3-4.5 hours were independent at 3 months: (57.5% vs. 60.3%, adjusted OR=0.84, 95% CI 0.75-0.95, p=0.005). 

Emberson et al. (2014) used data from 6,756 patients from 9 major t-PA trials (NINDs a/b, ECASS I/II, III, ATLANTIS a/b, EPITHET, IST-3) to examine the effect of timing of administration more closely. Earlier treatment was associated with the increased odds of a good outcome, defined as an (mRS score of 0-1 (≤3.0 h: OR=1.75, 95% CI 1.35-2.27 vs. >3 to ≤4.5 h: OR=1.26, 95% CI 1.05-1051 vs. >4.5 h: OR=1.15, 95% CI 0.95-1.40). Framed slightly differently, when patient-level data from the same 9 major randomized controlled trials (RCTs) were recently pooled, Lees et al. (2016) reported that for each patient treated within 3 hours, significantly more would have a better outcome (122/1,000, 95% CI 16-171), whereas for each patient treated >4.5 hours, only 20/1,000 (95% CI -31-75, p=0.45) would have a better outcome. Wardlaw et al. (2013), including the results from 12 RCTs (7,012 patients), concluded that for every 1,000 patients treated up to 6 hours following stroke, 42 more patients were alive and independent (mRS<2) at the end of follow-up, despite an increase in early ICH and mortality. The authors also suggested that patients who did not meet strict licensing criteria due to age and timing of treatment (i.e., patients from the IST-3) trial were just as likely to benefit; however, early treatment, within 3 hours of stroke onset, was more effective. 

Results from several recent trials indicate that thrombolysis with t-PA can be used for patients outside of the previously established therapeutic window. In the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial (Ma et al., 2019), 225 patients with an ischemic stroke were included, where symptom onset was estimated to be 4.5 to ≤9 hours previously. Recruitment was suspended after the results of the WAKE-UP trial became available. The primary outcome (mRS 0-1 at 90 days) occurred in 35.4% of the patients in the alteplase group and 29.5% in the control (placebo) group. After adjustment for age and baseline severity, the likelihood of the primary outcome significantly increased in the alteplase group (RR=1.44, 95% CI 1.01–2.06), as did the proportion of patients who attained a mRS score of 0-2 at 90 days (49.6% vs. 42.9%; adjusted RR=1.36, 95% CI, 1.06 to 1.76); however there was no significant difference between groups in functional improvement at 90 days (i.e., shift in mRS scores; RR=1.55, 95% CI 0.96 to 2.49). The results from the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke (WAKE-Up) trial (Thomalla et al., 2018) also suggest that highly selected patients with mild to moderate ischemic strokes and an unknown time of symptom onset, treated with alteplase may also benefit from treatment. Patients in this trial were not eligible for treatment with mechanical thrombectomy and were selected based on a pattern of DWI-FLAIR-mismatch. A significantly higher proportion of patients in the alteplase group had a favourable clinical outcome (mRS 0-1) at 90 days (53.3% vs. 41.8%, adj OR=1.61, 95% CI 1.06-2.36, p=0.02), although the risk of type 2 parenchymal hemorrhage was significantly higher compared with placebo (4% vs. 0.4%, adj OR=10.46, 95% CI 1.32 to 82.77, p=0.03).

The standard treatment dose of rt-PA is established to be 0.9 mg/kg, with a maximum dose of 90 mg. The non-inferiority of a lower dose (0.6 mg/kg) was recently examined in the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial (Anderson et al., 2016). The primary outcome (death or disability at 90 days) occurred in 53.2% of low-dose patients and 51.1% in standard-dose patients (OR=1.09, 95% CI 0.95-1.25, p for non-inferiority=0.51), which exceeded the upper boundary set for non-inferiority of 1.14. The risks of death within 90 days or serious adverse events did not differ significantly between groups (low dose vs. standard dose: 8.5% vs. 10.3%; OR=0.80, 95% CI 0.63-1.01, p=0.07 and 25.1% vs. 27.3%; OR=0.89, 95% CI 0.76-1.04, p=0.16, respectively), although the risk of symptomatic ICH was significantly higher in patients that received the standard dose of rt-PA.

Earlier treatment with thrombolytic agents is associated with better stroke outcomes. Using data from 61,426 Medicare patients aged ≥65 years admitted to Get With The Guidelines (GWTG)–stroke participating hospitals between January 1, 2006, and December 31, 2016, Man et al. (2020) found that among patients treated with intravenous alteplase, all-cause mortality was significantly higher in those that with door-to-needle times (DTN) of <45 minutes (vs. ≥45 minutes) and <60 minutes (vs. ≥60 minutes). The authors estimated that every 15-minute increase in DTN time was associated with a 4% increase in all-cause mortality within 90 minutes after hospital arrival, but not after 90 minutes, and a 2% increase in all-cause readmission. Analyzing data from the alteplase arm of seven major trials, the HEREMES Collaborators (Goyal et al., 2019) reported the common odds of a better outcome were decreased by each 60-minute delay in onset-to- treatment time (OTT) (OR=0.80, 95% CI 0.68–0.95). The odds of an excellent outcome (mRS 0-1) were also decreased by each 60-minute delay in OTT (OR=0.76, 95% CI 0.58–0.99).

Strategies to improve guideline adherence have been shown to help improve thrombolysis uptake and shorten thrombolysis process times. In Canada, following the initiation of an Improvement Collaborative intervention during 2016–2017, the number of patients receiving thrombolysis increased from 9.35% in the pre-period to 15.73% in the post-period, the median DTN time was reduced significantly from 70 to 39 minutes, and a significantly higher number of patients were discharged home in the post-period (46.5% to 59.5%) (Kamal et al., 2020). Using data from 71,169 patients admitted to 1,030 GWTG-participating hospitals, the outcomes and process times of patients admitted before and after the initiation of a quality improvement initiative (Target:Stroke) were examined (Fonarow et al., 2014). During that time the median DTN were reduced significantly from pre- to post- intervention (77 vs. 67 minutes, p<0.001), the percentage of patients treated within 60 minutes of stroke onset increased significantly from 26.5% to 41.3%, and in-hospital mortality decreased significantly from 9.93% to 8.25%. The percentage of patients discharged home also increased significantly from 37.6% to 42.7%.

The results from several studies indicate that tenecteplase, which has some pharmacokinetic advantages over alteplase, may be non-inferior to alteplase. Several clinical trials are ongoing and the results are not yet available. In these trials tenecteplase was compared with either alteplase (ATTEST2 NCT0281440) or placebo, or best medical management (TIMELESS NCT03785678, TWIST NCT03181360, and TEMPO-2 NCT02398656). Among completed trials comparing tenecteplase with alteplase, all were used as a potential bridging treatment prior to thrombectomy. The Alteplase Compared to Tenecteplase in Patients with Acute Ischemic Stroke (AcT) Trial (Mennon et al., 2022) was the first trial to report that tenecteplase is non-inferior to alteplase for 90-day functional outcomes. In this trial, 1,600 patients recruited from 22 centres who were eligible for treatment with alteplase (+/-thrombectomy) were randomized to receive intravenous tenecteplase (0.25mg/kg, maximum 25m) or 0.9 mg/kg alteplase. At a median of 97 days 36.9% of patients in the tenecteplase group achieved the primary outcome (mRS score of 0-1) vs.34.8% in the alteplase group (unadjusted difference=2.1%, 95% CI -2.6% to 6.9%; adjusted RR=1·1, 95% CI 1·0 to 1·2), meeting the non-inferiority threshold, (the lower bound 95% CI of which was set at >-5%). There was no significant difference between groups in mortality at 90 days (15.3% vs. 15.4%), or in the proportion with symptomatic ICH at 24 hours (3.4% vs. 3.2%). In contrast to these findings, the NOR-TEST 2 (Kvistad et al., 2022) was halted early due to safety concerns, which included an increased risk of intracranial hemorrhage and mortality; however, the dose in the tenecteplase group was higher (0.4 mg/kg) than is currently recommended (0.25 mg/kg). In the EXTEND-IA TNK (Campbell et al., 2018), which compared 0.25mg/kg tenecteplase vs. 0.9 mg/kg alteplase, at initial angiographic assessment, a significantly higher number of patients in the tenecteplase group achieved substantial reperfusion (22% vs. 10%, p=0.02 for superiority), although the percentage of patients who were functionally independent at 90 days or who had achieved an excellent outcome, did not differ between groups. 

The evidence base for the safety and effectiveness of the use of thrombolysis during pregnancy and the puerperium is derived from a series of case reports. The results from a total of 15 previous cases (10 intravenous and 5 intra-arterial), in addition to the presentation of their own case were summarized by Tversky et al. (2016). The neurological outcomes of these women were described as similar to non-pregnant patients who met the eligibility criteria. Most of the women who experienced significant recovery went on to deliver healthy babies. The evidence in terms of thrombolytic treatment for patients <18 years comes primarily from the International Pediatric Stroke Study (IPSS), an observational study (n=687) in which the outcomes of 15 children, aged 2 months to 18 years, who received thrombolytic therapy (9 with intravenous Alteplase, 6 with intra-arterial alteplase). Overall, at the time of hospital discharge, 7 patients were reported having no or mild neurological deficits, 2 had died, and the remainder had moderate or severe neurological deficits. The Thrombolysis in Pediatric Stroke (TIPS) study (Amlie-Lefond et al., 2009) is currently recruiting subjects for a five-year, prospective cohort, open-label, dose-finding trial of the safety and feasibility of intravenous and intra-arterial t-PA to treat acute childhood stroke (within 4.5 hours of symptoms). The TIPS investigators are aiming to include 48 subjects.

Sex and Gender Considerations

Possible interactions (treatment group x sex) were not analyzed in the initial reports of early trials of alteplase including NINDS (1995), ATLANTIS (1995), or ECASS (1995, 1998, 2008). The IST-III examined this relationship and reported there were no significant interactions based on sex, as did the authors of the ENCHANTED trial (2016) that examined low vs. standard dose alteplase. In more recent trials of late window treatment, including WAKE-UP (2018) and EXTEND (2019), the results of subgroup analyses based on sex were not conducted or reported. In the RCTs of tenecteplase including NOR-TEST 2 (2022), EXTEND-IA TNK (2018), and NOR-TEST (2017), the effect of treatment based on sex was not reported in subgroup analyses in the initial publications. Subgroup analysis for interactions based on sex for the AcT trial (2022) were conducted and no interactions were found.

Endovascular Thrombectomy

Over the past decade, the use of endovascular thrombectomy (EVT) for acute ischemic stroke has evolved, particularly in terms of patient selection criteria. Initially, EVT was limited to individuals with anterior circulation large vessel occlusion (LVO), small infarct core (ASPECTS ≥6), and treatment within a narrow time window (typically up to 6 hours from symptom onset). Compared with best medical management, the efficacy of EVT was established in landmark trials such as MR CLEAN, (Berkhemer et al. 2015) ESCAPE,(Goyal et al. 2015) and SWIFT PRIME. (Saver et al. 2015) Subsequent studies, including DAWN (Nogueira et al. 2018) and DEFUSE 3, (Albers et al. 2018) expanded eligibility to patients presenting up to 24 hours since last known well, provided there was a mismatch between clinical deficit and infarct core identified through advanced imaging. More recently, trials such as SELECT-2, (Albers et al. 2018) ANGEL-ASPECT, (Huo et al. 2023) and TENSION (Bendszus et al. 2023) have further broadened inclusion criteria by demonstrating the benefit of EVT in patients with large infarct cores (e.g., ASPECTS 3–5 or core volumes up to 100–150 mL). Treatment with EVT has been explored for the treatment of posterior artery infarctions (ATTENTION,(Hu et al. 2025) BAOCHE (Jovin et al. 2022) and BASICS (Langezaal et al. 2021)) and for medium and distal occlusions (ESCAPE-MeVO, (Goyal et al. 2025) DISTAL,(Psychogios et al. 2025) and DISCOUNT [NCT05030142]).

Several recent trials evaluated EVT in patients with medium-to-large core infarcts (ASPECTs 2-5) or high infarct core volumes. Traditionally these patients were considered poor candidates for reperfusion therapies. LASTE, (Costalat et al. 2024) TENSION, (Bendszus et al. 2023) ANGEL-ASPECT, (Huo et al. 2023) and SELECT-2, (Sarraj et al. 2023) trials all enrolled patients with anterior circulation LVO and low ASPECTS scores or large infarct volumes. LASTE included 333 patients with ASPECTS 0–5 (if less than 80 years old) identified on non-contrast CT, randomized within 6.5 hours of symptom onset. TENSION enrolled 253 patients with ASPECTS 3–5, on baseline computed tomography (CT) or diffusion-weighted imaging – magnetic resonance imaging (DWI-MRI) and occlusion defined by computed tomography angiography (CTA) or magnetic resonance angiography (MRA), treated within 12 hours. SELECT-2 (Sarraj et al. 2023) included 352 patients with ASPECTS 3–5 or infarct core measuring 50-100 mL using CT perfusion or diffusion-weighted MRI, with a treatment window of up to 24 hours. ANGEL-ASPECTS (Huo et al. 2023) included 456 patients with either an ASPECTS of 3–5 (regardless of core volume) or an ASPECTS of 0–2 with an infarct core volume of 70–100 mL, assessed within 24 hours of symptom onset. Additionally, patients with ASPECTS > 5 were included only if they had a core volume between 70–100 mL and presented between 6 and 24 hours after onset. All four of the trials were stopped early due to demonstrated efficacy of EVT at interim analysis, whereby EVT was associated with significantly improved functional outcomes (favourable shift in the distribution of mRS scores) at 90 days compared to best medical management alone. The benefit was consistent across subgroups, including those with ASPECTS as low as 3 and large core volumes. While symptomatic intracranial hemorrhage (sICH) occurred more frequently in the EVT group, overall mortality was either unchanged or reduced. The results were similar in RESCUE-Japan LIMIT, (Yoshimura et al. 2022) although the benefit was not as pronounced. The TESLA trial,(Yoo et al. 2024) included 300 patients with ASPECTS 2–5 up to 24 hours from last known well.  The mean average utility weighted mRS score at 90 days was not significantly different between the groups, nor was the percentage of patients with an mRS score of 0-2 at 90 days significantly higher in the EVT group (14.5% vs. 8.9%, RR=1.64, 95% CI 0.86-3.12); however, the percentage of patients with an mRS score of 0-3 at 90 days was significantly higher in the EVT group. Across all trials, the majority of patients (61%-69%) were dead or severely disabled at 90 days, despite EVT.

The use of EVT for medium vessel occlusions (MeVOs), including occlusions in the M2/M3 segments of the middle cerebral artery (MCA), anterior cerebral artery (ACA), and posterior cerebral artery (PCA) is a new area of interest.  While EVT is well established for anterior LVOs, its role in MeVOs remains under investigation. In the ESCAPE-MeVO trial, (Goyal et al. 2025) EVT in addition to best medical management was not associated with benefit compared with best medical management only, in 530 patients with occlusions located in the M2 segment of the proximal MCA (23.3%), M2 segment of the distal MCA (20.3%) and the M3 segment of MCA (41.4%). The median mRS score at 90 days was 2 in both groups. The likelihood of the primary outcome (mRS 0-1 at 90 days) was not significantly higher in the EVT group (adjusted common RR=0.95, 95% CI 0.79 to 1.15), nor was the likelihood of an mRS score of 0 -2 at 90 days (adjusted RR=0.92, 95% CI 0.80 to 1.05). Ninety-day mortality was significantly higher in the EVT group (13.3% vs. 8.4%, HR=1.82, 95% CI 1.06 to 3.12). The incidence of serious adverse events was higher in the EVT group (33.9% [in 87 patients]) than in the usual-care group (25.7% [in 70 patients]). In the DISTAL trial, (Psychogios et al. 2025) which included 543 patients with an isolated occlusion of medium or distal vessels (M2 [44.0%], M3 [26.9%], M1 [13.4%], P2 [13.4%], and P1 [5.5%] segments), there was no significant difference between groups in the distribution of mRS scores at 90 days (median mRS score was 2 vs. 2; common OR=0.90; 95% CI 0.67 to 1.22). Preliminary results from the DISCOUNT trial (NCT05030142), which was terminated early following the first interim analysis also suggests potential harm associated with EVT treatment. The primary outcome (mRS 0-2 at 90 days) occurred in 45/75 patient (60%) in the EVT group vs. 59/77 (77%) in the usual care group (adjusted OR=0.42, 95% CI 0.2-0.88). Additionally, sICH occurred in 12% of the patients in the EVT group vs. 6% in the usual care group.

Intra-arterial thrombolysis administered following EVT may help to dissolve residual thrombus in distal vessels, potentially improving microvascular reperfusion and functional outcomes, without significantly increasing the risk of sICH. However, in the POST-UK(Liu et al. 2025) and POST-TNK (Huang et al. 2025) trials, patients with anterior circulation LVO infarcts, who achieved near complete or complete reperfusion following EVT and who received intra-arterial thrombolysis post procedure, with either tenecteplase or urokinase, did not have a higher likelihood of achieving an mRS score of 0-1 at 90 days compared with patients who did not receive thrombolysis, nor did thrombolysis reduce the risk of 90-day mortality. In contrast, preliminary results presented at the International Stroke Conference in 2025, from the PEARL trial (NCT05856851) indicated that patients with anterior circulation LVO infarcts who achieved near complete or complete reperfusion (expanded Thrombolysis in Cerebral Infarction score of 3 or 2b50) following EVT, and received thrombolysis with either tenecteplase or alteplase post EVT had higher likelihood of having an mRS score of 0-1 at 90 days (44.8% vs 30.2%; RR=1.45, 95% CI 1.08-1.96), with no increased risk of sICH within 36 hours or 48 hours. Intra-arterial thrombolysis post EVT did not increase the likelihood of freedom from disability at 90 days in patients with posterior circulation strokes in the ATTENION-IA trial.(Hu et al. 2025) 

For large artery occlusions in the posterior circulation, 4 RCTs have compared EVT with best medical management only, with conflicting results. In the ATTENTION trial (Tao et al. 2022) which included 342 patients, recruited  <12 hours from onset with NIHSS ≥10, a significantly higher percentage of patients in the EVT group achieved an mRS score of 0-3 compared with those in the medical management group (46.0% vs. 22.8%; adjusted RR= 2.06, 95% CI 1.46 to 2.91, NNT=4). Ninety-day mortality was also lower (36.7% vs. 55.3%: adj RR= 0.7,95% CI 0.5 to 0.8, NNT=5.4). A benefit of EVT was also demonstrated in the BAOCHE trial, (Jovin et al. 2022) which included 217 patients enrolled within 6–24 hours after symptom onset and NIHSS ≥6. In contrast, Liu et al. (Liu et al. 2020) included 131 adult patients presenting within 8 hours of vertebrobasilar occlusion to 28 centres in China in the BEST trial. The trial was terminated early due to excessive crossovers and low enrollment. In the intention-to-treat analysis, the percentage of patients with a favourable outcome (mRS 0-3) at 90 days was not significantly higher in the intervention group (42% vs. 32%; adjusted [age and baseline NIHSS] OR=1.74, 95% CI 0.81–3.74, p=0.23), nor was the percentage of patients who were functionally independent; however, in both the per protocol and as treated analyses, the percentage of patients with a favourable outcome was significantly higher in the EVT group. There was no significant difference between groups in 90-day mortality or in sICH. The BASICS trial recruited 300 patients with basilar artery occlusion. (Langezaal et al. 2021) Intravenous alteplase was used in close to 80% of patients in both the EVT and control groups. The percentage of patients in the EVT group who experienced a favourable (mRS 0-3) or excellent (mRS 0-2) outcome at 90 days was not significantly higher in the EVT group. The results of these two RCTs and three observational studies were pooled in a systematic review by Katsanos et al. (Katsanos et al. 2021) With low certainty of evidence, there was no significant difference found between the groups for the primary outcome of mRS score 0–3 at 90 days (RR= 0.97, 95% CI: 0.64-1.47). There were no significant differences between groups for the proportion of patients with mRS scores of 0-2 at 3 months, all-cause mortality or functional outcome (ordinal shift analysis of mRS scores), with significant heterogeneity. The risk of sICH was significantly higher in the EVT group (RR=5.42, 95% CI 2.74-10.71).

To date, 6 RCTs have been published comparing direct EVT with intravenous alteplase prior to EVT for LVO infarcts (i.e., bridging), with conflicting results. The most recent trials, DIRECT SAFE (Mitchell et al. 2022) and SWIFT DIRECT (Fischer et al. 2022) both reported that EVT alone was not shown to be non inferior to EVT plus thrombolysis. For the primary outcome of mRS score of 0-2 at 90 days, the adjusted differences in proportions between groups were −7.3% (95% CI −16.6 to 2.1, p=0·12) in the SWIFT-DIRECT trial and −5.1% (95% CI −16 to 5.9, p=0.19) in the DIRECT SAFE trial, which crossed the lower boundaries of the two-sided 95% confidence interval set for non-inferiority at 12% and 10%, respectively. Two previously published trials, the SKIP trial (Suzuki et al. 2021) and MR CLEAN–NO IV trial, (LeCouffe et al. 2021) also did not demonstrate the non-inferiority of EVT alone. In the MR CLEAN–NO IV trial, the adjusted common odds ratio (OR) for shift in mRS score at 90 days was 0.84 (95% CI 0.62 to 1.15), which showed neither superiority nor noninferiority of EVT alone. In the SKIP trial, (Suzuki et al. 2021) mechanical thrombectomy alone was not associated with a favorable shift in the distribution of the mRS score at 90 days (OR=0.97, 1-sided 97.5% CI 0.60 to ∞; noninferiority p =0.27, which crossed the 0.74 threshold). In contrast, DIRECT-MT (Yang et al. 2020) and DEVT (Zi et al. 2021) reported that EVT alone was non-inferior to alteplase followed by EVT. In the DEVT trial, 54.3% of patients in the EVT group achieved functional independence vs. 46.6% in the bridging group (difference= 7.7%; 1-sided 97.5% CI −5.1% to ∞; p = .003 for noninferiority, threshold for non-inferiority was -10%). Finally, EVT alone was noninferior to bridging in an ordinal shift analysis of mRS scores at 90 days (adjusted common OR=1.07; 95% CI 0.81 to 1.40; p=0.04 for noninferiority) in the DIRECT-MT trial. (Yang et al. 2020) In a systematic review and patient-level meta-analysis including the results from all 6 RCTs described above, (Majoie et al. 2023) non-inferiority of EVT alone was not established. For an average patient, the estimated difference in probability of reaching functional independence (mRS 0-2) at 90 days when omitting intravenous thrombolysis was –2.5% (95% CI –6.5% to 1.0%). Thrombolysis prior to EVT using tenecteplase has also been evaluated. In the BRIDGE-TNK trial, (Qiu et al. 2025) the likelihood of achieving an mRS score of 0-2 at 90 days was significantly higher in patients who received tenecteplase (0.25 mg/kg) prior to EVT compared with those who did not (52.9% vs. 44.1%; adjusted RR=1.18, 95% CI 1.01–1.39).

Sedation
There have been a limited number of RCTs specifically comparing the use of general anesthesia versus conscious sedation for EVT procedure. The results are conflicting. Results from the AMETIS trial, (Chabanne et al. 2023) indicated that conscious sedation increased the probability of a good outcome (mRS 0-2) at 90 days by 29%, while 10.9% of the conscious sedation patients converted to general anesthesia. Previous single-centre trials including GOLIATH, (Simonsen et al. 2018) AnStroke Trial, (Löwhagen Hendén et al. 2017) and SIESTA (Schönenberger et al. 2016) trials, reported that general anesthesia was associated with better outcome (mRS 0-2) at 90 days. The conversion from conscious sedation to general anesthesia in these trials occurred in 6.3%, 14.3% and 15.5% of patients. Preliminary results from the SEdation Versus General Anesthesia for Endovascular Therapy in Acute Ischemic Stroke (SEGA, NCT03263117), also suggest that general anaesthesia was associated with a significantly higher likelihood of functional independence measured by mRS at 90 days (OR=1.22).

A systematic review (Campbell et al. 2021) including the results of 3 RCTs (GOLIATH, AnStroke and SIESTA) in addition to data from a pilot study of 40 patients, (Sun et al. 2020) found the odds of successful recanalization and good functional outcome were significantly higher in the general anesthesia group (OR=2.14, 95% CI 1.26-3.62, p=0.005 and OR=1.71, 95% CI: 1.13-2.59; P=0.01, respectively), with no significant differences between groups in the risk of mortality or intracerebral hemorrhage. A Cochrane review (Tosello et al. 2022) included the results from 7 RCTs and reported on both short and long-term outcomes. In the short-term, general anesthesia was not associated with better early neurological recovery or stroke related mortality, but was associated with a decreased risk of adverse events and greater likelihood of artery revascularisation. The likelihood of having a good functional outcome (mRS ≤2) at 90 days was not significantly higher in the general anesthesia group.

The outcomes of patients who received general anesthesia or conscious sedation has also been examined within the landmark EVT trials. Using the results from 7 RCTs including MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, PISTE and THRACE,  Campbell et al. (Campbell et al. 2018) performed a patient-level meta-analysis comparing the outcomes of patients randomized to the EVT groups who had received general anesthesia or non-general anesthesia.  The odds of improved outcome using non-general anesthesia were significantly higher in ordinal analysis of mRS scores. The authors estimated for every 100 patients treated under general anesthesia (compared with non-general anesthesia), 18 patients would have worse functional outcome, including 10 who would not achieve functional independence. There was no increased risk of 90-day mortality associated with general anesthesia.

Sex and Gender Considerations

In a patient-level meta-analysis using data from 5 RCTs, conducted by the HERMES Collaborators, (Goyal et al. 2016) there were no significant treatment effects of EVT based on pre-specified subgroups including age, sex, NIHSS, site of intracranial occlusion, intravenous alteplase received or ineligible, ASPECTS, time from onset to randomization, or the presence of tandem cervical carotid occlusion. The same finding was reported in another Hermes Collaboration, using data from 7 RCTs, (Chalos et al. 2019) which was confined to an examination of sex differences. No evidence of heterogeneity of treatment effect based on sex was detected in prespecified subgroups in the DEFUSE 3 trial, (Albers et al. 2018) DAWN trial, (Nogueira et al. 2018) ESCAPE, (Goyal et al. 2015) or THRACE(Bracard et al. 2016) trials, where subgroup analysis was performed. In the two, most recent trials examining  EVT with bridging therapy, (DIRECT SAFE, (Mitchell et al. 2022)  and SWIFT DIRECT (Fischer et al. 2022)), differences in sexes between treatment groups were examined in prespecified subgroup analyses; none were found. Sex differences were examined specifically in 3,422 patients included in the IRETAs database who had undergone EVT treatment since 2011.(Casetta et al. 2022) The outcomes of women vs. men were compared in the original cohort (1,621 men and 1,801 women) and in a propensity-matched cohort of 1,150 men and women. In both the whole cohort and matched-pair cohort, the odds of functional independence at 90 days given EVT treatment were significantly higher in women (OR= 1.19, 95% CI 1.02–1.38 and OR=1.25, 95% CI 1.04-1.51, respectively). Time metrics (e.g., onset to groin puncture) were similar for men and women. Kobeissi et al.(Kobeissi et al. 2023) included 10 studies (10,209 patients) treated with EVT. There was no significant difference between the sexes in the odds of achieving the primary outcome (mRS 0-2 at 90 days: OR= 1.16, 95% CI 0.87-1.56), nor were there any differences between groups on any of the secondary outcomes (mRS 0-1, sICH, thrombolysis in cerebral infarction (TICI) score of 2b-3, and mortality).

Note: The CSBPR Acute Stroke Management writing group and the National Advisory Committee strongly endorse all of the recommendations in Section 5, based on available research evidence, clinical expertise, and international consensus. A recent technology assessment report provided a focused assessment of some of these data and suggested there is “substantial uncertainty” regarding the effectiveness of alteplase; however, this technology report did not synthesize all the available evidence and their conclusions differ from most other international guideline organizations as well as the CSBPR writing group. Refer to evidence table (CADTH, 2022).