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.

Pour les cas d’AVC ischémique dans une artère importante de la circulation antérieure, le traitement endovasculaire s’est avéré efficace, avec un NST de quatre, approximativement, pour atteindre l’autonomie fonctionnelle après 90 jours. En fait, des données de l’essai DAWN (Nogueira et coll., New Eng J Med 2018;378:11-21) indiquent que le NST pourrait être aussi bas que trois. Les résultats regroupés d’essais plus anciens indiquent au contraire que ce nombre serait plus proche de cinq (HERMES, Goyal et coll., Lancet 2016;387(10029):1723-31). Ce type de traitement peut avoir des effets extrêmement positifs sur les patients ayant subi un AVC ischémique particulièrement dévastateur qui, sans traitement, seraient condamnés à rester invalides.  

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. Il convient de renforcer les capacités des neuro-interventionnistes dûment formés au sein des régions sanitaires et des établissements universitaires 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 avoir été bien communiqués à tous les professionnels de la santé de l’hôpital relativement à la prise en charge des patients hospitalisés 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. Il faut assurer l’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 de patients traités 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 TDM 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 » 
• Voir l’encadré 5C : « Critères d’inclusion pour la thrombectomie endovasculaire » 
• 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 »
• Cœur + AVC,  « Liste de vérification du protocole relatif à la thrombectomie endovasculaire 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

Re-vascularization can also be achieved through mechanical dislodgement with specialized devices (+/- intra-arterial and/or intravenous rt-PA). To date, over 10 major RCTs have been completed for which results have been published, in which endovascular therapies were compared with best medical management. Several trials are still ongoing or have yet to report their findings (e.g., TENSION NCT03094715; MR CLEAN-LATE ISRCTN 19922220). The recent results from most of these trials indicate that rapid endovascular therapy is a safe and more effective treatment than intravenous t-PA alone, for patients with anterior circulation ischemic strokes in selected regions, when performed within 6 to 24 hours of symptom onset. 

In the one of the earliest trials, MR CLEAN (Berkhemer et al., 2014), included 500 adult patients with a baseline NIHSS score of 2 or greater, and who were treatable within 6 hours of stroke onset. Patients were randomized to receive endovascular treatment with rt-PA or urokinase, and/or mechanical treatment with retrievable stents, which were used in 81.5% of patients, or other available devices, versus best medical management. The median time from stroke onset to groin puncture was 260 minutes. The majority of patients in both groups were treated with intravenous t-PA (87.1% intervention group, 90.6% control group). There was a significant shift in the distribution towards more favourable mRS scores among patients in the intervention group at 90 days (adj common OR=1.67, 95% CI 1.21-2.30). The odds of both a good (mRS 0-2) and excellent (mRS 0-1) recovery at day 90 were also significantly higher among patients in the intervention group (adj OR=2.07, 95% CI 1.07-4.02 and adj OR=2.16, 95% CIU 1.39-3.38, respectively). Patients in the intervention group were more likely to have a lower median final infarct volume (-19 mL, 95% CI 3-34, n=298). At two-year follow-up (van den Berg et al., 2017), the odds of an mRS score of 0-2 remained significantly higher in the intervention group (37.1% vs. 23.9%, adj OR= 2.21, 95% CI 1.30−3.73, p=0.003). The ESCAPE trial (Goyal et al., 2015) enrolled 316 patients ≥18 years, with stroke onset <12 hours, a baseline NIHSS score of >5 and moderate-to-good collateral circulation. Patients were randomized to receive endovascular mechanical thrombectomy, using available devices or best medical management. The median time from stroke onset to first reperfusion was 241 minutes. 72.7% of patients in the intervention group and 78.7% of those in the control group received intravenous t-PA. The odds of improvement in mRS scores by 1 point at 90 days were significantly higher among patients in the intervention group (adj OR=3.2, 95% CI 2.0-4.7). The odds of good outcome (mRS score 0-2) at 90 days were also higher in the intervention group (adj OR=1.7, 95% CI 1.3-2.2), as were the odds of a NIHSS score of 0-2 and a Barthel Index score of 95-100 (adj OR=2.1, 95% CI 1.5-3.0 and 1.7, 95% CI 1.3-2.22, respectively). The risk of death was significantly lower in the intervention group (adj RR=0.5, 95% CI 0.-0.8). In neither MR CLEAN nor ESCAPE, was there an increased risk of symptomatic ICH associated with endovascular therapy. No interaction effects were found in subgroup analyses of age, stroke severity, time to randomization, or baseline ASPECTS in either of the trials.

The THRACE trial (Bracard et al., 2016) had broader eligibility criteria and included 414 patients aged 18 to 80 years with an occlusion in the intracranial carotid, the MCA (M1) or the upper third of the basilar artery with onset of symptoms <4 hours and NIHSS score of 10-25 at randomization. Patients were randomized to receive dual intravenous t-PA therapy plus intra-arterial mechanical clot retrieval with the Merci, Penumbra, Catch, or Solitaire devices or treatment with IV rt-PA only. The median time from symptom onset to thrombectomy was 250 minutes. The odds of achieving mRS score of 0-2 at 90 days were increased significantly in the thrombectomy group (53% vs. 42.1%, OR=1.55, 95% CI 1.05-2.3, p=0.028, NNT=10). There were no significant differences between groups in the number of patients with symptomatic or asymptomatic hemorrhages at 24 hours. Three trials evaluated the efficacy of the use of a specific retriever device (Solitaire FR Revascularization Device). In the EXTEND IA trial (Campbell et al., 2015), there were no inclusion criteria related to stroke severity. Seventy patients ≥18 years, with good premorbid function and an anterior circulation acute ischemic stroke, with criteria for mismatch, who could receive intra-arterial treatment within 6 hours of stroke onset, were included. All patients received intravenous rt-PA, while 35 also underwent intra-arterial mechanical clot retrieval. A significantly greater proportion of patients in the endovascular group experienced early neurological improvement (80% vs. 37%, p<0.001), >90% reperfusion without ICH at 24 hours (89% vs. 34%, p<0.001), and were functionally independent at day 90 (71% vs. 40%, p=0.009). The SWIFT-PRIME trial (Saver et al., 2015) randomized 196 patients, aged 18 to 80 years with NIHSS scores of 8-29 with a confirmed infarction located in the intracranial internal carotid artery, MCA, or carotid terminus who could be treated within 6 hours of onset of stroke symptom, to receive intravenous rt-PA therapy plus intra-arterial mechanical clot retrieval, or rt-PA only. The likelihood of successful reperfusion (>90%) at 27 hours was significantly higher in the endovascular therapy group (82.8% vs. 40.4%, RR=2.05, 95% CI 1.45-2.91, p<0.001) and a significantly higher percentage of patients were independent (mRS 0-2) at day 90 (60.2% vs. 35.5%, RR=1.70, 95% CI 1.23-2.33, p=0.001). Finally, in the REVASCAT trial (Jovin et al. 2015), 206 patients with NIHSS scores ≥6 who could be treated within 8 hours of stroke onset were randomized to receive mechanical embolectomy plus best medical management, or best medical management only, which could include intravenous t-PA (78%). The odds of dramatic neurological improvement at 24 hours increased significantly in the intervention group (adj OR=5.8, 95% CI 3.0-11.1). The odds for improvement by 1 mRS point at 90 days were increased significantly in the intervention group (adj OR=1.7, 95% CI 1.05-2.8), as were the odds of achieving an mRS score of 0-2 at 90 days (adj OR=2.1, 95% CI 1.1-4.0). At one-year follow-up (Davalos et al., 2017), the proportion of patients who were functionally independent (mRS score 0–2) was significantly higher than for patients in the thrombectomy group (44% vs. 30%; OR=1.86, 95% CI 95% CI 1.01-3.44). No treatment effects were noted based on subgroup analyses in either SWIFT-PRIME or REVASCAT, based on age, baseline NIHSS score, site of occlusion, time to randomization, or ASPECTS score. There was no increased risk of symptomatic ICH in any of these trials. 

The results of the DAWN (Nogueira et al., 2018) and DEFUSE-3 (Albers et al., 2018) trials indicate that the treatment window for mechanical thrombectomy is wider than previously thought. The DAWN trial included 206 patients, last been known well 6 to 24 hours earlier, with no previous disability (mRS 0-1) and who met clinical mismatch criteria who had either failed intravenous t-PA therapy, or for whom its administration was contraindicated because of late presentation. Patients were randomized to treatment with thrombectomy with Trevo device plus medical management, or medical management alone. The trial was terminated early after interim analysis when efficacy of thrombectomy was established. The median intervals between the time that a patient was last known well and randomization was 12.2 hours in the thrombectomy group and 13.3 hours in the control group. The mean utility weighted mRS score was significantly higher in the thrombectomy group (5.5 vs. 3.4, adj difference =2.0, 95% Cr I 1.1-3.0, prob of superiority >0.999). There were no interactions in subgroup analysis (mismatch criteria, sex, age, baseline NIHSS score, occlusion site, interval between time that patient was last known well and randomization and type of stroke onset). A significantly higher proportion of patients in the thrombectomy group experienced an early response to treatment, had achieved recanalization at 24 hours, and were independent (mRS 0-2) at 90 days (49% vs. 13%, NNT=3). The admission criteria for the DEFUSE-3 trial were broader and included those who had remaining ischemic brain tissue that was not yet infarcted. The median time from stroke onset to randomization was just under 11 hours for patients in the endovascular group. A significantly higher proportion of patients in the endovascular group were independent (mRS 0-2) at 90 days (45% vs. 17%, OR=2.67, 95% CI 1.60–4.48, p<0.001, NNT=4). 

The results from several meta-analyses that pooled the results from these major trials indicate better outcomes were associated with mechanical thrombectomy. A recent Cochrane review (Roaldsen et al., 2021) included the results from 19 RCTs (3,793 participants). Treatment with EVT was associated with a significantly higher likelihood of favourable outcome (RR=1.61, 95% CI 1.42 to 1.82) with a high certainty of evidence, without a significantly increased risk of symptomatic ICH (RR=1.46, 95% CI 0.91 to 2.36). A pooled analysis of 6 RCTs including DAWN, DEFUSE 3, ESCAPE, RESILIENT, POSITIVE and REVASCAT also found significantly better outcomes in patients in the EVT group (Jovin et al., 2021). The was a significant shift in the ordinal analysis of mRS scores favouring less disability in the thrombectomy group (adj OR=2·54, 95% CI 1·83–3·54) with stronger effects noted with earlier treatment.

For large artery occlusions in the posterior circulation, the data are limited with the results from two RCTs in which EVT was compared with best medical management. Liu et al. (2020) included 131 adult patients presenting within 8 hours of vertebrobasilar occlusion to 28 centres in China in the Basilar Artery Occlusion Endovascular Intervention versus Standard Medical Treatment (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 symptomatic intracerebral hemorrhage (sICH). The Basilar Artery International Cooperation Study (BASICS) trial recruited 300 patients with basilar artery occlusion (Langezaal et al., 2021). Intravenous alteplase was used in close to 80% of patients in 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. (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 (shift analysis), 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 (i.e., bridging). The most recent trials, SWIFT DIRECT (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 non-inferiority of EVT alone. In the SKIP trial, mechanical thrombectomy alone was not associated with a favourable shift in the distribution of the mRS score at 90 days (OR=0.97, 1-sided 97.5% CI, 0.60 to ∞; non-inferiority p = .27, which crossed the 0.74 threshold). In contrast, DIRECT-MT (Yang et al., 2021) 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 non-inferiority, threshold for non-inferiority was -10%). Finally, EVT alone was non-inferior 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 non-inferiority) in the DIRECT-MT trial.

There have been a limited number of RCTs specifically comparing the use of general anesthesia versus conscious sedation for EVT procedure. Preliminary results of one of the most recent trials the Anesthesia Management in Endovascular Therapy for Ischemic Stroke (AMETIS) trial (NCT03229148), indicate that conscious sedation increased the probability of a good outcome (mRS 0-2) at 90 days by 29%. Previous single-centre trials including the General or Local Anesthesia in Intra Arterial Therapy (GOLIATH, Simonsen et al., 2018), Anesthesia During Stroke (AnStroke Trial, Löwhagen Hendén et al., 2017) and Sedation vs. Intubation for Endovascular Stroke Treatment (SIESTA, Schönenberger et al., 2016), 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%. The results of the SEdation Versus General Anesthesia for Endovascular Therapy in Acute Ischemic Stroke (SEGA, NCT03263117) are expected in early 2023. A systematic review including the results of all three aforementioned trials plus data from a pilot study of 40 patients (Campbell et al., 2021) 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 greater in the general anesthesia group. The outcomes of patients who received general anesthesia or conscious sedation has also been examined in the context of EVT RCTs. Using the results from 7 RCTs including MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, PISTE and THRACE, Campbell et al. (2018) performed a patient-level meta-analysis comparing the outcomes of patients randomized to the mechanical thrombectomy 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 (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 randomisation, 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. Subgroup analyses based on sex were not conducted for the primary outcome in the RESCUE-Japan LIMIT (2022) or REVESCAT (Jovin et al. 2015) trials, although other potential effect modifiers (e.g. age, baseline NIHSS score) were examined. 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 (2016) trial, where subgroup analysis was performed. In the two, most recent trials examining direct EVT with bridging therapy, (DIECT 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. 

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).