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Thérapie thrombolytique en phase aiguë

5e édition
2015 MISE À JOUR
juin 2015

La 5e édition des Recommandations canadiennes pour les pratiques optimales de soins de l’AVC sur les soins de l’AVC en phase hyperaiguë (2015) est publiée dans l’International Journal of Stroke et est accessible en ligne gratuitement. Afin d’accéder aux recommandations spécifiques pour : Thérapie thrombolytique en phase aiguë et tous les autres chapitres des recommandations sur les soins de l’AVC en phase hyperaiguë, veuillez cliquer sur ce lien, qui vous dirigera vers les recommandations en ligne dans l’Internal Journal of Stroke : http://onlinelibrary.wiley.com/doi/10.1111/ijs.12551/full.

Pour la version française de ces recommandations, veuillez ouvrir l’annexe au lien suivant : http://onlinelibrary.wiley.com/store/10.1111/ijs.12551/asset/supinfo/ijs12551-sup-0001-si.zip?v=1&s=cdf3d494242426450aaa522f104ace17857f037a

Tous les autres renseignements connexes, y compris les indicateurs de rendement, les ressources de mise en l’œuvre, les résumés des données probantes et les références, sont accessibles au www.pratiquesoptimales.ca, et non pas sur le site de l’International Journal of Stroke. Veuillez cliquer sur les sections appropriées de notre site Web pour le contenu additionnel.

Encadré 4.3 : Critères de sélection par imagerie endovasculaire

Principes de la sélection par imagerie

Utiliser l’imagerie pour sélectionner les patients qui présentent les trois critères suivants pour le traitement :

  1. Un noyau ischémique de taille petite à modérée.
    1. Un noyau ischémique de taille petite à modérée est défini par une note ASPECTS de 6 ou plus lors d’une TDM sans injection de produit de contraste ou d’un volume sanguin cérébral déterminé par imagerie de perfusion par TDM.
  2. Une occlusion d’une artère intracrânienne proximale de la circulation antérieure, une lésion cible pouvant faire l’objet du traitement endovasculaire.
    1. L’emplacement de l’occlusion est défini par une phase artérielle d’angiographie CT de l’aorte ascendante au vertex. L’inclusion des structures de l’aorte permet de planifier et d’évaluer la faisabilité technique de l’approche endovasculaire sur l’artère intracrânienne occluse.
  3. Des preuves d’une circulation collatérale de modérée à bonne de la pie-mère définie par une angiographie CT multiphase ou dynamique, ou alors d’une disparité de perfusion par TDM. Voir le tableau récapitulatif : Comparaison des éléments clés des essais cliniques endovasculaires récents.
Justification

Les méta-analyses des essais cliniques randomisés portant sur l’administration du t-PA par voie intraveineuse pour l’AVC ischémique aigu révèlent que le traitement thrombolytique peut réduire le risque d’incapacités et de décès, malgré le risque d’une hémorragie grave. Le dernier moment après l’apparition de l’AVC auquel il est encore opportun d’administrer le t-PA n’est pas encore défini avec précision. Toutefois, les données dont on dispose indiquent que l’administration produit des effets bénéfiques jusqu’à 4,5 heures après l’apparition des symptômes. Les données probantes disponibles démontrent une relation inversement proportionnelle entre le délai avant le traitement et les résultats cliniques. Les patients admissibles devraient être traités sans délai, quel que soit le créneau temporel dans lequel ils se présentent.

Pour les cas d’AVC ischémique dans une artère importante, le traitement endovasculaire s’est avéré efficace avec un nombre approximatif de sujets à traiter de quatre pour atteindre l’autonomie fonctionnelle après 90 jours. Ce traitement a un effet important sur les patients qui ont subi les AVC ischémiques les plus dévastateurs, des patients qui, si on ne les traitait pas, auraient alourdi considérablement le fardeau sur le système de santé et les aidants naturels.

Exigences pour le système

  • Des protocoles locaux qui priorisent les patients qui ont fait un AVC afin de leur accorder un accès immédiat au diagnostic approprié, y compris l’imagerie par TDM et l’imagerie neurovasculaire avec angiographie CT. Cette approche doit concerner aussi bien les patients dont on connaît le moment de début des symptômes (ou le dernier moment auquel ils ont été vus dans leur état normal) que ceux chez lesquels les symptômes ont été remarqués au réveil.
  • La disponibilité d’appareils de TDM hélicoïdale qui ont été adéquatement programmés pour l’angiographie CT (multiphase ou dynamique) et les séquences de perfusion par TDM, ainsi que des logiciels de post-traitement adéquats, optimisés pour la production d’images de haute qualité.
  • Des systèmes de soins coordonnés et intégrés auxquels participent tout le personnel pertinent pour les soins des patients qui ont fait un AVC en phase hyperaiguë, y compris les ambulanciers, le personnel de l’urgence, les équipes de l’AVC, les radiologues et les spécialistes en neuro-intervention. 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 le créneau temporel du traitement.
  • La régionalisation du savoir-faire en neurologie et en neuro-intervention de l’AVC, avec un système 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 l’administration du t-PA par voie intraveineuse, ainsi que sur le transport à des centres de niveau de soins de l’AVC plus élevé pour l’administration du t-PA par voie intraveineuse et le traitement endovasculaire, au besoin.
  • Des protocoles de phase hyperaiguë en place qui ont été bien communiqués à tous les professionnels de la santé de l’hôpital au sujet de la prise en charge des patients qui ont subi un AVC hospitalisés et assurant l’accès à la TDM cérébrale ainsi qu’à l’angiographie CT des vaisseaux extracrâniens et intracrâniens dès que possible après le début des symptômes.
  • L’accès à des unités de l’AVC spécialisées dont les membres ont déjà pris en charge des patients qui avaient reçu du t-PA ou un traitement endovasculaire.
  • Les programmes d’intervention endovasculaire sont évoluent partout au Canada; les décisions relatives au site, aux protocoles de transfert 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 par les ambulanciers à ces établissements devront être prises à l’échelle provinciale ou régionale, et communiquées à tous les intervenants pertinents.
Indicateurs de rendement

  1. La proportion globale de patients qui ont fait un AVC ischémique et qui sont traités avec le t-PA par voie intraveineuse (prioritaire).
  2. Le délai médian (en minutes) entre l’arrivée d’un patient à l’urgence et l’administration du t-PA par voie intraveineuse.
  3. Le délai médian entre l’arrivée à l’hôpital et la ponction de l’aine, ainsi qu’entre la TDM (première tranche de la TDM sans injection de produit de contraste) et la ponction de l’aine pour les patients qui suivent le traitement endovasculaire.
  4. La proportion des patients qui ont subi un AVC ischémique qui reçoivent le traitement de t-PA par voie intraveineuse dans les 3 et les 4,5 heures du début des symptômes.
  5. La proportion de tous les patients victimes d’un AVC ayant fait la thrombolyse qui ont reçu le t-PA dans les 30 minutes après leur arrivée à l’hôpital (prioritaire).
  6. La proportion globale de patients qui ont fait un AVC ischémique et qui reçoivent le traitement endovasculaire (prioritaire).
  7. Le délai médian entre l’arrivée à l’hôpital et la reperfusion pour les patients qui font le traitement endovasculaire. Le temps de reperfusion doit être défini comme la première image d’angiographie illustrant une reperfusion partielle ou totale du territoire artériel touché. Dans bien des cas, cette occurrence coïncidera avec la première utilisation d’une endoprothèse récupérable.
  8. Pour les patients qui ont fait un AVC alors qu’ils étaient à l’hôpital pour d’autres raisons médicales, le délai médian entre la dernière fois où le patient a été vu dans son état normal et l’imagerie cérébrale.
  9. Pour les patients qui ont fait un AVC alors qu’ils étaient à l’hôpital pour d’autres raisons médicales, le délai médian entre la dernière fois où le patient a été vu dans son état normal et le traitement thrombolytique en phase aiguë ou le traitement endovasculaire (ponction de l’aine).
  10. L’état de reperfusion final pour les patients faisant le traitement de reperfusion endovasculaire, quantifié à l’aide du système Modified Thrombolysis in Cerebral Infarction (mTICI).
  11. La proportion de patients atteints d’hémorragie sous-arachnoïdienne ou intracérébrale symptomatique après l’administration du t-PA par voie intraveineuse (définie comme un cas PH1, PH2, RIH, SAH ou IVH associé à une dégradation d’au moins quatre points sur l’échelle NIHSS dans les 24 heures).
  12. La proportion de patients atteints d’hémorragie sous-arachnoïdienne ou intracérébrale symptomatique après le traitement endovasculaire (définie comme un cas PH1, PH2, RIH, SAH ou IVH associé à une dégradation d’au moins quatre points sur l’échelle NIHSS dans les 24 heures).
  13. La proportion de patients de collectivités rurales ou éloignées chez lesquels le t-PA est administré avec l’aide de la technologie télé-AVC (par rapport à tous les patients qui ont fait un AVC ischémique dans ces collectivités et par rapport à toutes les consultations par télé-AVC pour AVC ischémique).
  14. La note Modified Rankin Scale (mRS) de tous les patients ayant subi un AVC qui reçoivent le t-PA par voie intraveineuse ou qui obtiennent le traitement endovasculaire au moment du congé de l’hôpital ainsi que 90 jours après ce congé.
  15. Le taux de décès à l’hôpital (global et sur 30 jours) pour les patients victimes d’un AVC ischémique, stratifié en fonction de l’obtention ou non du t-PA ou du traitement endovasculaire.

Notes relatives à la mesure des indicateurs

  • Données extraites des dossiers médicaux des patients par examen ou vérification.
  • La mesure du délai devrait débuter au triage ou à l’admission du patient à l’hôpital (le premier des deux prévalant) et se terminer lorsque le t-PA est administré, selon l’heure inscrite dans le dossier du patient (dossiers de soins infirmiers, de l’urgence ou des médicaments).
  • Pour les indicateurs de rendement 4 et 5, calculer tous les percentiles, puis examiner le 50e et le 90e, ainsi que l’intervalle entre les quartiles.
  • En notant l’administration de t-PA, il faut préciser la voie d’administration puisque les étalons de référence temporels pour l’administration intraveineuse et intra-artérielle diffèrent.
  • Le temps de traitement endovasculaire doit correspondre à l’heure de la première ponction de l’aine.
Ressources pour la mise en œuvre et outils d’application des connaissances

Information à l’intention des dispensateurs de soins de santé

Information à l’intention du patient

Résumé des données probantes

Evidence Table 4A Acute Thrombolytic Therapy

Evidence Table 4B Endovascular Therapy

Section 4 Comparison of Endovascular Treatment Trials

The weight of evidence from many large, international trials over a time frame of 20 years suggests that treatment with intravenous tissue Plasminogen Activator (tPA) can reduce the risk of death or disability following ischemic stroke at 3 to 6 months post-treatment. Since the fall of 2014, five major clinical trials of endovascular therapy with mechanical embolectomy were completed with results demonstrating significant improvement in patient outcomes based on the modified Rankin scale score at 90 days post-treatment, with one trial also demonstrating decreased mortality with endovascular therapy (Goyal et al, 2015; Campbell et al. 2015; Berkhemer et al, 2014; Saver et al, 2015, Davalos et al 2015).

Intravenous Thrombolysis

The NINDS trial (1995) was one of the earliest, large trials, which was conducted in the USA. Patients were randomized to receive Alteplase or placebo within 3 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 4 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 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 3-6 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 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 (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 to 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 advance age or time to treatment. Unlike all previous, large trials, which excluded them, IST-3 included patients >80 years. In fact, the majority of patients (53%) were >80 years. 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 sub groups 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).

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 3-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 hour of symptom onset (n=11,865) and those treated from 3-4.5 hours (n=644). The primary focus of this analysis was to assess treatment safety beyond the 3-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 3-4.5 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). A meta-analysis restricted to RCTs patients from the ECASS I, II and III and ATLANTIS trials (n=1,622) who had received Alteplase or placebo 3 to 4.5 hours following stroke suggested a benefit of treatment (Lansberg et al. 2009). Patients who had received Alteplase had a significantly greater likelihood of a favourable outcome (OR=1.31, 95% CI 1.1-1.56, p=0.002) and were no more likely to be dead at 90 days. OR=1.01, 95% CI 0.75-1.43, p=0.83). Outcome data for ICH were not reported. Most recently, 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 more closely examine the effect of timing of administration. 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).

An updated systematic review and meta-analysis of intravenous thrombolysis (Wardlaw et al. 2013) that included the results from 12 RCTs (7,012 patients), published from 1992-2012 strengthen the evidence that treatment with t-PA is safe and effective. The authors 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.

The use of thrombolytic therapy in patients who are younger than 18 years and in women at any stage of pregnancy has not been evaluated empirically. Twelve case reports of women who received thrombolysis treatment constitute the evidence base for this group. The results from 11 cases have been summarized by Li et al. (2012) and the 12th case report was published recently (Tassi et al. 2013). In 4 cases, t-PA was administered using the intra-arterial route. The neurological outcomes of these women were described as being similar to (non-pregnant) patients who met the eligibility criteria. 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 5-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.

The results of a recent feasibility study, TEMPO-1 (Coutts et al. 2015), suggest that Tenecteplase (TNK-tissue-type plasminogen activator) may be a safe and effective treatment for minor stroke and TIA. In this open-label study, 55 patients, previously independent with NIHSS score ≤5 with an event occurring within the previous 12 hours, received a single dose of intravenous TNK-t-PA of 0.1 mg/kg or 0.25 mg/kg. The incidence of symptomatic ICH and mortality were low, while 46% of all patients treated experienced complete recanalization at 24 hours following treatment and 90% experienced a good outcome (mRS 0-2) at 90 days.

Intra-arterial Thrombolysis & Endovascular Therapy

Re-vascularization can also be achieved through intra-arterial administration of thrombolytic agents or mechanical dislodgement with specialized devices. The body of evidence for these procedures is not as well developed as it is for intravenous thrombolysis. A meta-analysis (Fargen et al. 2014) included the results of 6 RCTs (PROACT II, MELT, IMS III, SYNTHESIS, MR. RESCUE and MR. CLEAN, n=1,903) comparing endovascular therapies with best medical management following ischemic stroke. Using the results from 5 studies that included patients with large-vessel occlusions, endovascular therapy was associated with significantly improved odds of a good (mRS 0-2) and excellent (mRS 0-1) recovery at 90 days (OR=1.67, 95% CI 1.29-2.16, and OR=1.93, 95% CI 1.39-2.68, respectively. There was also a positive shift in mRS scores (mean 3.35 vs. 3.73, p<0.0001), but no significant decrease in mortality (OR=0.80, 95% CI 0.60-1.07). When all 6 trials were included, the pattern of results was similar, although the odds of an excellent recovery were not significantly improved (OR=1.22, 95% CI 0.97-1.53).

The recent results from 5 multi-centered RCTs suggest that rapid endovascular therapy may be a safe and more effective treatment than intravenous t-PA only for patients with anterior circulation ischemic strokes in selected regions when performed within 6-12 hours of symptom onset. In the largest of these trials, MR CLEAN (Berkhemer et al. 2014), and the only one which was not stopped early due to efficacy, 500 patients were recruited who were ≥18 years, with a baseline NIHSS score of 2 or greater, and were treatable within 6 hours of stroke onset. Patients were randomized to receive endovascular treatment with t-PA or urokinase, and/or mechanical treatment with retrievable stents or other available devices or best medical management only, which could include intravenous t-PA. Retrievable stents were used in 81.5% of patients assigned to the endovascular therapy group. 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 show no evidence of intracranial occlusion on follow-up CTA (adj OR=6.88, 95% CI 4.34-10.94, n=394) and to have a lower median final infarct volume (-19 mL, 95% CI 3-34, n=298).

The ESCAPE trial (Goyal et al. 2015) enrolled 316 patients ≥18 years, with stroke onset less than 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.

Three trials evaluated the efficacy of the use of a specific device for clot retrieval (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 t-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 randomized 196 patients, aged 18-80 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 t-PA therapy + intra-arterial mechanical clot retrieval, or t-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 at day 90 (mRS 0-2) (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 of 6 or greater who could be treated within 8 hours of stroke onset were randomized to receive mechanical embolectomy + best medical management or best medical management only, which could include intravenous t-PA. The odds of dramatic neurological improvement at 24 hours were 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). No treatment effects were noted based on sub group 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 positive results from these 5 trials contrast with those of earlier RCTs examining endovascular therapy. In the SYNTHESIS trial, Ciccone et al. (2013) randomized 362 patients to receive either pharmacological or mechanical thrombolysis, or a combination of these approaches or intravenous t-PA within 4.5 hours of symptom onset. At 90 days, the percentages of patients alive, living without disability were similar between groups (30.4% vs. 34.8%, adjusted OR=0.71, 95% CI 0.44 to 1.14, p=0.16). There were no differences in adverse events between groups (death or ICH). The IMS III trial (Broderick et al. 2013), which also randomized patients to receive mechanical or pharmacological endovascular treatment, or intravenous t-PA was stopped early due to a lack of efficacy. Reasons that have been cited for the lack of positive findings in these trials include the use of older style devices, the prolonged time to initiation of intra-arterial treatment and the lack of pre-treatment vascular imaging. The hypothesis that patients with a favorable penumbral pattern, may benefit preferentially from endovascular treatment compared with those with a nonpenumbral pattern was not supported in the MR RESCUE trial (Kidwell et al. 2013). Patients were randomized within 8 hours of symptom onset to undergo mechanical embolectomy with the Merci Retriever or Penumbra System, or standard care, grouped according to penumbra pattern vs. nonpenumbra pattern. At 90 days, there were no significant differences between groups (embolectomy vs. standard care) in the mean mRS score, the proportion of patients with a good outcome (mRS 0-2) or death among patients with penumbral or nonpenumbral patterns. The authors suggested that the low rates of recanalization may have been one of the contributors to the null findings.