Thérapie thrombolytique en phase aiguë *Nouveau!

Ces critères visent à orienter les décisions cliniques; toutefois, la décision d’administrer le tPA dans ces situations dépend du jugement clinique du médecin traitant.

Critères adaptés de ceux formulés par le National Institute of Neurological Disorders and Stroke (NINDS) et l’European Cooperative Acute Stroke Study (ECASS III, IST3).

Critères de traitement :

• Diagnostic d’AVC ischémique avec déficits neurologiques mesurables chez un patient âgé d’au moins 18 ans
  • Chez les adolescents la décision devrait reposer sur le jugement clinique, les symptômes présents et l’âge du patient, si possible en consultation avec un spécialiste de l’AVC pédiatrique.
• Délai depuis la dernière fois vu dans son état normal à l’administration de tPA <4,5 heures

Critères d’exclusion :

Antécédents

• antécédents d’hémorragie intracrânienne au cours des six derniers mois
• AVC ou traumatisme crânien ou cervical au cours des trois derniers mois
• chirurgie majeure récente – cardiaque, thoracique, abdominale ou orthopédique
• ponction artérielle à un endroit non compressible au cours des sept derniers jours
• tout autre trouble de la santé qui pourrait augmenter le risque d’hémorragie après l’administration de tPA

Cliniques

• symptômes évocateurs de la présence d’une hémorragie sous-arachnoïdienne
• symptômes de l’AVC dus à un autre trouble neurologique non ischémique aigu, par exemple crises épileptiques suivies de paralysie de Todd ou signes neurologiques focaux dus à une hypoglycémie ou hyperglycémie grave
• hypertension résistante aux antihypertenseurs empêchant d’atteindre une tension artérielle cible <185/110 mm Hg

Résultats de laboratoire

• glycémie 2,7 mmol/L ou 22,2 mmol/L
• temps de thromboplastine partielle élevée
• RIN (rapport international normalisé) 1,7
• numération plaquettaire 100 000/mm3 (ou 100 x 109/L)

Résultats de TDM ou IRM

• présence d’hémorragie intracrânienne
• signes précoces d’infarctus vaste, soit un score 5 sur l’échelle ASPECTS (Alberta Stroke Program Early CT Score), ou IRM pondérée par diffusion révélant un volume d’infarctus supérieur à 150 cc

Les méta-analyses d’essais cliniques comparatifs sur échantillon aléatoire portant sur l’administration d’alteplase par voie intraveineuse pour l’AVC ischémique aigu révèlent que la thérapie thrombolytique peut réduire le risque d’invalidité 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 de l’alteplase n’est pas encore défini avec précision. Toutefois, les données dont on dispose indiquent que l’administration d’alteplase produit des effets bénéfiques jusqu’à 4,5 heures après l’apparition des symptômes. Les données probantes disponibles démontrent une inversion 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.

• Protocoles locaux visant à donner aux patients avec AVC un accès rapide en priorité au diagnostic par des moyens tels que la TDM et l’ultrasonographie duplex, communiqués à tout le personnel approprié de l’urgence, du service d’imagerie et des équipes de l’AVC
• Systèmes assurant l’accès rapide à des médecins spécialisés en administration d’agents thrombolytiques en phase aiguë de l’AVC, y compris par le truchement de la télémédecine, notamment des protocoles pour rejoindre les médecins et pour administrer l’activateur tissulaire du plasminogène (tPA)
• Accès à des unités spécialisées en AVC dans lesquelles le personnel possède l’expérience de la prise en charge de patients qui ont reçu du tPA pour un AVC

1. Proportion des patients avec AVC ischémique traités à l’alteplase par voie intraveineuse (prioritaire)
2. Proportion des patients avec AVC ischémique se présentant moins de 3,5 heures après l’apparition des symptômes recevant de l’alteplase
3. Proportion des patients avec AVC ischémique thrombolysés recevant de l’alteplase moins d’une heure après leur arrivée à l’hôpital (prioritaire)
4. Délai médian (en minutes) entre l’arrivée du patient à l’urgence et l’administration d’alteplase
5. Proportion des patients avec hémorragie intracérébrale symptomatique suite à un traitement à l’alteplase
6. Proportion des patients vivant dans des communautés rurales ou éloignées recevant de l’alteplase par le truchement de la télémédecine (en tant que proportion de tous les cas d’AVC ischémique dans cette communauté et des consultations par TéléAVC pour les cas d’AVC ischémique)

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 au moment où l’administration du médicament est notée au dossier du patient (notes du personnel infirmier, dossier de l’urgence ou dossier des médicaments)
• En notant l’administration de tPA il faut préciser la voie d’administration puisque les étalons de référence temporels pour l’administration intraveineuse et intra-artérielle diffèrent.

• Canadian Stroke Best Practices Patient Order Set of Initial Emergency Department Evaluation of a Suspected Stroke Patient
• Canadian Stroke Best Practices Patient Order Set for tPA (Alteplase) administration
• Canadian Stroke Best Practices Table 3.3A Screening and Assessment Tools for Acute Stroke
• Canadian Stroke Best Practices Implementation Guide: Taking Action Towards Optimal Stroke Care
• HSF Stroke Nurses Assessment Pocket Cards
• American College of Chest Physicians (ACCP) Anticoagulation Guidelines

The weight of evidence from many large, international trials over a time frame of 20 years suggests that treatment with intravenous Alteplase can reduce the risk of death or disability following ischemic stroke, 3 to 6 months post treatment. 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 tPA 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 tPA 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.

An updated systematic review and meta-analysis of intravenous thrombolysis (Wardlaw et al. 2013) that included the results from 12 RCTs (7,012 patients) of tPA, published from 1992-2012 strengthen the evidence that treatment with tPAis 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, tPA 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 tPA to treat acute childhood stroke (within 4.5 hours of symptoms). The TIPS investigators are aiming to include 48 subjects.

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 (Nam et al. 2013) included 6 RCTs examining the treatment contrasts of intraarterial thrombolysis (IAT) and either standard treatment (n=4) or intravenous thrombolysis (n=2) following acute ischemic stroke. Treatment with IAT was associated with the reduction of poor functional outcome at end of follow-up (RR=0.83, 95% CI 0.73 to 0.94, p=0.004), compared with standard treatment. Although the risk of ICH was increased (RR=3.90, 95% CI 1.41 to 10.76, p = 0.009), mortality was not (RR=0.82, 95% CI 0.56 to 1.21, p = 0.32). In the two studies that compared IAT with i.v. tPA, there was a trend towards the reduction in poor outcome associated with IAT (RR = 0.68, 95% CI 0.46 to 1.00, p=0.05). The rates of ICH and mortality between groups were similar. 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 ii) intravenous tPA within 4.5 hours of symptom onset. Patients in both groups received a tPA dose of 0.9 mg/kg (max dose 90 mg). At 90 days, the percentages of patients alive without disability was 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).

Evidence Table 3.4 and References