Taille du texte :    +   -

Traitement antiplaquettaire des cas d’AVC ischémique et d’AIT

2017 MISE À JOUR
octobre 2017

Remarque : Ces recommandations s’appliquent en cas d’AVC ischémique et d’ischémie cérébrale transitoire.

6.1 Un traitement antiplaquettaire devrait être prescrit pour tous les patients avec AVC ischémique ou AIT en prévention secondaire, à moins qu’une anticoagulation soit indiquée [niveau de preuve A].

  1. L’acide acétylsalicylique (AAS) (80 à 325 mg), l’association AAS (25 mg) et dipyridamole à libération prolongée (200 mg), et le clopidogrel (75 mg) sont tous des choix appropriés et leur sélection devrait dépendre du contexte clinique [niveau de preuve A].
    1. Les études sur l’utilisation concomitante à court terme d’acide acétylsalicylique et de clopidogrel (jusqu’à 21 jours) n’ont pas démontré une augmentation du risque hémorragique, et cette combinaison pourrait constituer une protection à la suite d’un AVC ou d’une ischémie cérébrale transitoire mineurs [niveau de preuve B] ;
    2. L’utilisation à long terme de l’acide acétylsalicylique et du clopidogrel n’est pas recommandée pour la prévention secondaire de l’AVC, à moins qu’il y ait une autre indication (p. ex., endoprothèse à élution médicamenteuse exigeant un double traitement antiplaquettaire), à cause d’un risque accru d’hémorragie et de mortalité [niveau de preuve A]. Cette combinaison d’efficacité fait actuellement l’objet d’une étude dans le cadre de l’essai POINT (www.clinicaltrials.gov ; identifiant NCT00991029).

6.2 Considérations en matière d’AVC pédiatrique :

  1. La dose d’entretien en vue de la prévention d’une récidive chez les enfants victimes d’un AVC traités à l’AAS est de 3 à 5 mg/kg/j [niveau de preuve B]. La dose maximale habituelle chez les adolescents est de 81 mg/jour.
    1. Il n’existe aucune donnée probante concernant la durée optimale du traitement ; la décision devrait être fondée sur les circonstances cliniques individuelles.
  2. Les données probantes relatives à l’utilisation du clopidogrel chez les enfants sont présentement rares. Le clopidogrel est une solution de rechange envisageable chez les adolescents à une dose de 1 mg/kg/j jusqu’à un maximum de 75 mg/j, particulièrement dans le contexte d’une allergie à l’AAS. Les jeunes enfants ont parfois un effet antiplaquettaire plus important en prenant du clopidogrel ; la dose recommandée devrait se situer dans l’éventail de 0,2-0,5 mg/kg/j [niveau de preuve C].

Considérations cliniques : (Nouveau depuis 2016)

  1. Pour l’heure, il n’y a pas suffisamment de données probantes pour guider la prise en charge du patient qui est victime d’un AVC alors qu’il suit un traitement antiplaquettaire. Dans tous les cas de récidive d’AVC pendant un traitement antiplaquettaire, les facteurs de risque vasculaire et l’étiologie de l’AVC doivent être évalués et vigoureusement pris en charge.
  2. L’opinion des experts suggère que si un patient subit un AVC alors qu’il prend de l’AAS, il peut être raisonnable d’envisager de passer au clopidogrel ; si un patient subit un AVC alors qu’il prend du clopidogrel, il peut être raisonnable d’envisager de passer à une combinaison d’acide acétylsalicylique (25 mg) et de dipyridamole à libération prolongée (200 mg).

Voir la section 7 de la prévention de l’AVC sur l’AVC et la fibrillation auriculaire pour d’autres recommandations relatives au traitement antithrombotique.

La version définitive de cet article a été publiée dans l’International Journal of Stroke par SAGE Publications Ltd. © World Stroke Organization, 2017.
http://journals.sagepub.com/doi/suppl/10.1177/1747493017743062/suppl_file/supplementary_material.pdf

Justification

Les agents antiplaquettaires sont considérés comme incontournables dans la prévention de l’AVC secondaire. Plusieurs essais cliniques ont démontré que les antiplaquettaires (dont l’AAS) réduisent le risque d’épisodes vasculaires ultérieurs après un AVC ischémique ou un AIT (une baisse de 25 % du risque relatif). Cet effet modeste est utile sur le plan clinique parce qu’il montre que les antiplaquettaires sont bien tolérés par la majorité des patients avec AVC ischémique ou AIT. Les essais comparant différents schémas posologiques d’antiplaquettaires concluent à de toutes petites différences en ce qui a trait à l’efficacité absolue ; leur choix est par conséquent équivoque.

Exigences pour le système
  • Cliniques de prévention de l’AVC accessibles dans chaque communauté visant à améliorer la prévention secondaire (prévention efficace et cohérente accompagnée d’un dépistage précoce des facteurs de risque et d’interventions ciblées amorcées en temps opportun).
  • Optimisation de stratégies locales, régionales et provinciales de grande portée visant la prévention des récidives de l’AVC.
  • Sensibilisation à la prévention de l’AVC et formation en prévention secondaire à l’intention des fournisseurs de soins primaires et des spécialistes qui prennent en charge des patients avec AVC en phase aiguë et après leur congé des soins actifs.
Indicateurs de rendement
  1. Proportion des patients avec AVC ischémique aigu ou AIT qui reçoivent un agent antiplaquettaire moins de 48 heures après leur arrivée à l’hôpital.
  2. Proportion des patients avec AVC ischémique ou AIT à qui on a prescrit un traitement antiplaquettaire lorsqu’ils ne reçoivent plus de soins actifs.
  3. Proportion des patients avec AVC ischémique ou AIT à qui on a prescrit un traitement antiplaquettaire lorsqu’ils ne reçoivent plus de soins en clinique de prévention secondaire.

Notes sur la mesure des indicateurs

  • Sources de données : Dossier médical du patient, notes du personnel infirmier, ordonnances des médecins et résumés produits au moment du congé. La qualité de la documentation peut restreindre la possibilité de surveiller précisément cet indicateur de rendement.
  • En milieu de soins primaires, la mesure de l’observance et des habitudes de prescription des ordonnances risque d’être difficile.
  • Certains patients suivent déjà un traitement anticoagulant et pourraient être exclus. Voir les mesures additionnelles pour toutes les ordonnances d’antithrombotiques dans le Manuel sur la mesure du rendement de la Stratégie canadienne de l’AVC (www.canadianstrokestrategy.ca).
  • Il faut préciser au moment de la collecte de données les raisons pour lesquelles les patients admissibles n’ont pas reçu d’ordonnance d’antiplaquettaires. Ces renseignements aident à interpréter les résultats des indicateurs de rendement et à orienter les initiatives d’amélioration de la qualité.
Ressources pour la mise en Å“uvre et outils de transfert des connaissances

Renseignements destinés aux dispensateurs de soins de santé

Informations destinées au patient

Résumé des données probantes

Antiplatelet Therapy Evidence Tables and Reference List

Substantial evidence from randomized trials and meta-analyses supports the use of antithrombotic agents in patients who have experienced an ischemic stroke or TIA to reduce the risk of future events. The most commonly recommended antiplatelet agents for secondary stroke prevention in North America and Europe are acetylsalicylic acid (ASA, 75 to 325 mg/day), clopidogrel, and the combination of ASA and extended-release dipyridamole.

ASA Monotherapy
A meta-analysis conducted by The Antithrombotic Trialists’ Collaboration (2002) included the results of 287 RCTs (n=135,000) examining any antiplatelet therapy for the prevention of vascular events in high-risk patients. In 9 of these trials, long-term aspirin monotherapy was examined in patients who had experienced a previous stroke or TIA. In these trials, fewer patients receiving aspirin therapy experienced a vascular event (8.2% vs. 9.1%) representing an 11% odds reduction. In 65 trials examining aspirin monotherapy across doses ranging from <75mg to 1.500 mg, the mean percentage odds reduction of any vascular event was 23%. ASA and other forms of antiplatelet drugs reduced the incidence of nonfatal stroke by one-quarter. The Antithrombotic Trialists’ Collaborative (ATTC) included the results of 18 RCTs examining aspirin therapy for primary (n=6 with 95,456 subjects) and secondary (n=16) prevention of vascular events (Baigent et al. 2009). In the primary prevention trials, there was a significant reduction in risk of any serious vascular event, but no significant reduction in the risk of stroke (RR=0.95, 95% CI 0.85-1.06, p=0.40), fatal stroke (RR=1.21, 95% CI 0.84-1.74) or nonfatal stroke (RR=0.92, 95% CI 0.79-1.07). Secondary prevention trials were associated with a reduced risk of stroke of unknown cause (RR=0.77, 95% CI 0.62-0.96), but no reduction in the risk of ischemic stroke (RR=0.78, 95% CI 0.57-1.06) or fatal stroke (RR=1.08, 95% CI 0.73-1.62).

Ticagrelor
While aspirin at varying doses is the most widely-used antiplatelet agent, the risk of hemorrhagic events, particularly gastrointestinal bleeding, remains substantial. The use of another agent, ticagrelor, a P2Y12 receptor inhibitor, has recently been studied as a potentially safer alternative to aspirin. In the Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial (Johnston et al. 2016), 13,199 patients who had experienced a minor stroke or high-risk TIA within the previous 24 hours were randomized to receive either ticagrelor or aspirin. At the end of 90 days, there were no significant differences between groups on the primary, secondary or safety outcomes between groups, indicating that ticagrelor was not superior to aspirin.

Dual vs. Monotherapy with Clopidogrel
Several large clinical trials have examined the combination of clopidogrel + aspirin vs. aspirin alone. While the results from some of these trials failed to demonstrate a significant further reduction in risk of recurrent stroke associated with dual therapy among patients who had already sustained a minor stroke or TIA, most reported an increased risk of bleeding events. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial randomly assigned 15,603 patients with clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg/day) plus low-dose ASA (75 to 162 mg/day) or placebo plus low-dose ASA, with a median follow-up of 28 months (Bhatt et al. 2006). There was a non-significant reduction in the risk of the primary outcome (a composite of nonfatal stroke, nonfatal myocardial infarction or vascular death) associated with dual therapy (6.8% vs. 7.3%, RR=0.93, 95% CI 0.83-1.05, p=0.22). There were also non-significant reductions in death from any cause, death from cardiovascular causes and non-fatal MI associated with dual therapy. There was a significant reduction in the risk of all nonfatal stroke (1.9% vs. 2.4%, RR=0.79, 95% CI 0.64-0.98, p=0.03), but not nonfatal ischemic stroke (1.7% vs. 2.1%, RR=0.81, RR=0.64-1.02, p=0.07). More patients in the dual therapy group experienced moderate bleeding (2.1% vs. 1.3%, p<0.001) but there was no difference between groups in other adverse events (severe and fatal bleeding and ICH). The investigators concluded that, clopidogrel plus ASA was not significantly more effective than ASA alone in reducing the rate of myocardial infarction, stroke or vascular death. Similar results were reported in the Fast Assessment of Stroke and TIA to prevent Stroke Recurrence (FASTER) trial (Kennedy et al. 2007) where there was a non-significant reduction in the risk of stroke associated with clopidogrel use (7.1% vs. 10.8%, RR=0.7, 95% CI 0.3-1.2, p=0.19) and a significant 3% increase in risk (p=0.03) for symptomatic bleeding events in the groups allocated to clopidogrel. In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, patients were randomized to receive 325 mg of enteric coated aspirin + 75 mg clopidogrel daily or aspirin + placebo (Benavente et al. 2012). After a mean follow-up period of 3.4 years, the addition of clopidogrel was not associated with reductions in stroke, MI or death from vascular causes, but it was associated with an increased risk of all-cause mortality. A subgroup analysis that included patients who were on aspirin therapy at the time of the qualifying stroke demonstrated that the addition of 75 mg clopidogrel was not associated with reductions in the risk of stroke or MI, but was associated with a significant increase in death from any cause and vascular death (Cote et al. 2014). One recent major trial that did report a benefit of the addition of clopidogrel was the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, in which investigators randomized 5,170 patients with minor ischemic stroke within 24 hours or high-risk TIA to receive clopidogrel (75 mg/day) plus low-dose ASA (75 mg/day) or clopidogrel placebo plus aspirin for 90 days (Wang et al. 2013). Significantly fewer patients in the clopidogrel + aspirin group experienced a stroke within 90 days (Any stroke: 8.2% vs. 11.7%, HR=0.68, 95% CI 0.0.57-0.81, p<0.001) or an MI, stroke or vascular death stroke (8.4% vs. 11.9%, HR=0.69, 95% CI 0.58- 0.82, p<0.001). There was no difference in (any) bleeding events between groups (2.3% vs. 1.6%, p=0.09). A recently published meta-analysis included the results from 13 RCTs (Palacio et al. 2015). Overall, the use of clopidogrel+ aspirin was associated with significantly reduced odds of any stroke (OR=0.81, 95% CI 0.74-0.89). The odds were reduced for patients with stable vascular disease (OR=0.82, 95% CI 0.69-0.97) and for patients with a recent vascular event (OR=0.84, 95% CI 0.72-0.98). However, the use of dual therapy was associated with a significant increase in the odds of major hemorrhage (OR=1.40, 95% CI 1.26-1.55). Among the 4 RCTs that included patients with recent ischemic stroke (CARESS, CHARISMA, CLAIR, FASTER), the odds of all stroke were significantly reduced (OR=0.67, 95% CI 0.46-0.97), while the odds of major hemorrhage were not significantly increased (OR=0.91, 95% CI 0.40-2.07).

A single, large trial has examined the treatment contrast of clopidogrel + aspirin vs. clopidogrel alone (Deiner et al. 2004). The Management of Atherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic stroke (MATCH) trial included 7,599 high-risk patients with recent ischemic stroke or transient ischemic attack and at least one additional vascular risk factor. All patients received 75 mg of clopidogrel daily; In addition, patients were randomized to receive 75 mg aspirin daily or placebo, daily for 18 months. The addition of aspirin did not reduce the occurrence of the primary outcome (a composite of ischemic stroke, myocardial infarction, vascular death or rehospitalization for acute ischemia:16% vs. 17%, Absolute Risk Reduction=6.4%, 95% CI -4.6%-16.3%, p=0.244), or the incidence of fatal/nonfatal stroke and vascular death (11% vs. 11%, ARR=0.75%, 95% CI -0.7%-2.2%, p=0.324) or any stroke (9% vs. 9%, ARR=0.20%, 95% CI -1.1%-1.55, p=0.79). The investigators concluded that the addition of ASA was associated with a nonsignificant reduction in major vascular events and a significant increase in the risk of life-threatening or major bleeding.

The use of clopidogrel among children for the prevention of stroke recurrence has not been well-studied. Soman et al. (2006) followed 17 children, aged 1 month to 17 years, for up to 4 years after arterial ischemic stroke. Children were started on clopidogrel after demonstrating failure or intolerance to aspirin. There were no cases of stroke recurrence during a mean follow-up of 1.8 years. No patient receiving monotherapy with clopidogrel reported any major complications, while two patients reported minor complications (hand numbness and headache) that were not thought to be medication related. Among 9 patients who received aspirin in addition to clopidogrel, there were 2 cases of intracranial bleeding.

Dual vs. Monotherapy with Dipyridamole
Dipyridamole is another antiplatelet agent that can be combined with aspirin for the prevention of stroke. The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) randomized 2,763 patients who had experienced a TIA or minor stroke within the previous 6 months to receive extended-release dipyridamole (200 mg bid) + aspirin (30 to 325 mg/d-mean dose, 75 mg, n=1,363) or aspirin (as above) alone for 3.5 years. Significantly fewer patients in the dual therapy group experienced the primary outcome (composite of vascular death, nonfatal stroke, nonfatal MI or major bleeding complication: 12.7% vs. 15.7%, HR=0.80, 95% CI 0.66-0.98, NNT=104), all-cause mortality or nonfatal stroke. Patients taking ASA and dipyridamole discontinued trial medication more often than those on ASA alone (34% vs. 26%), mainly because of headache. A recent systematic review and meta-analysis (Wong et al. 2013) included the results of 3 RCTs (ESP-2, ESPRIT & EARLY) examining the risk of stroke recurrence associated with dipyridamole + aspirin vs. aspirin alone. There was a non-significant reduction in the risk of stroke recurrence associated with dual therapy (RR=0.64, 95% CI 0.37-1.10, p=0.80).

A single trial has examined the effectiveness of an non-aspirin comparator as the single agent in a dual agent trial (Sacco et al. 2008). The Prevention Regimen for Effectively avoiding Second Stroke (PRoFESS) trial, randomized 20,332 patients, who had experienced an ischemic stroke within the previous 90 days to receive 25 mg aspirin + 200 mg extended release dipyridamole (ERDP) twice daily or 75 mg clopidogrel daily, for 4 years. There was no difference in the number of patients who experienced stroke, MI or vascular death between group (13.1% in each group, HR=0.99, 95% CI 0.92-1.07). Stroke recurrence rates were similar in both arms of the trial (9.0% among patients assigned to receive ASA plus extended-release dipyridamole and 8.8% among patients assigned to receive clopidogrel; HR 1.01, 95% CI 0.92–1.11). More patients in the ERDP group experienced a major hemorrhagic event (4.1% vs. 3.6%, HR=1.15, 95% CI 1.00-1.32) or an intracranial hemorrhage (0.9% vs. 0.5%, HR=1.08, 95% CI 1.11-1.83).