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

Les agents antiplaquettaires sont considérés comme incontournables dans la prévention secondaire de l’AVC. Plusieurs essais cliniques ont révélé la capacité des antiplaquettaires (dont l’AAS) à réduire le risque de subir d’autres accidents vasculaires après un AVC ischémique ou un AIT (réduction de 25 % du risque relatif). Cet effet modeste est utile sur le plan clinique parce que les antiplaquettaires sont bien tolérés par la plupart des patients ayant subi un AVC ischémique ou un AIT. Les essais comparant différents schémas posologiques d’antiplaquettaires concluent à de toutes petites différences en ce qui a trait à l’efficacité absolue, ce qui rend le choix difficile.  

Nombreuses sont les victimes d’un AVC, et leur famille, à s’inquiéter du traitement anticoagulant, de ses risques et de ses effets indésirables potentiels. Ces personnes ont souvent l’impression de ne pas savoir comment gérer correctement ces agents antiplaquettaires, et comptent souvent sur leur pharmacien comme principale source d’information sur les médicaments antiplaquettaires qui leur ont été prescrits. Ils affirment également que c’est la façon la plus rapide et la plus facile d’obtenir des renseignements sur leurs médicaments. Les personnes ayant subi un AVC aimeraient qu’on les informe sur les antiplaquettaires, et qu’on répète l’information au besoin, notamment sur les raisons pour lesquelles ces médicaments leur sont prescrits et sur les facteurs de risque associés. Elles se plaignent de difficultés au moment de consulter plusieurs spécialistes qui leur donnent parfois des renseignements contradictoires, notamment à propos de ces médicaments. Ces constats font ressortir la nécessité d’une bonne planification de la transition et de stratégies efficaces de communication entre les spécialistes et les médecins de famille, dans le dessein d’améliorer l’observance du traitement, d’assurer la sécurité en matière de prise en charge des médicaments, de prévenir les erreurs et de réduire les événements indésirables.

1. Cliniques de prévention de l’AVC accessibles dans chaque collectivité afin d’améliorer la prévention secondaire (entre autres par la prévention efficace et cohérente au moyen d’un dépistage précoce des facteurs de risque et par des interventions ciblées amorcées en temps opportun).
2. Services de prévention coordonnés et complets offerts par les fournisseurs de soins primaires et mécanismes visant à s’assurer que l’enjeu du risque d’AVC est abordé à chaque consultation d’un professionnel de la santé dans le continuum des soins.
3. Amélioration de la communication et de la planification de la transition entre toutes les étapes et tous les milieux de soins afin que les membres de l’équipe de soins primaires soient pleinement informés des objectifs des soins et des traitements préventifs amorcés par les fournisseurs de soins lors des premières évaluations (p. ex., au service d’urgence); rendez-vous de suivi visant à poursuivre les examens et prise en charge à long terme du patient.  
4. Optimisation de stratégies locales, régionales et provinciales de grande portée visant la prévention des récidives d’AVC.
5. Sensibilisation à la prévention des AVC et formation en prévention secondaire à l’intention des fournisseurs de soins primaires et des spécialistes qui prennent en charge des personnes atteintes d’un AVC en phase aiguë, puis après leur congé du service des soins actifs.

1. Proportion des patients atteints d’un AVC ischémique en phase aiguë ou d’un AIT qui reçoivent un agent antiplaquettaire en phase aiguë moins de 48 heures après leur arrivée à l’hôpital.
2. Proportion des patients ayant subi un AVC ischémique ou un AIT à qui on a prescrit un traitement antiplaquettaire au moment de leur congé du service des soins actifs..
3. Proportion des patients ayant subi un AVC ischémique ou un AIT à qui on a prescrit un traitement antiplaquettaire au moment de leur congé des consultations de soins de prévention secondaire.

Notes sur la mesure des indicateurs

• Sources possibles 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 aura peut-être une incidence sur la possibilité de surveiller avec précision cet indicateur de rendement
• En milieu de soins primaires, il peut s’avérer difficile de mesurer l’observance du traitement et les habitudes de prescription
• Certains patients qui reçoivent déjà des anticoagulants pourraient se voir exclus de ces mesures. Reportez-vous aux 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).
• Au moment de la collecte des données, il faut préciser les raisons pour lesquelles les patients admissibles n’ont pas reçu d’ordonnance d’antiplaquettaires. Ces renseignements aident à interpréter les résultats de la mesure des indicateurs de rendement et à orienter les initiatives d’amélioration de la qualité.

Renseignements destinés aux dispensateurs de soins de santé

• Cœur + AVC – Liste de vérification 
• Recommandations canadiennes pour les pratiques optimales de soins de l’AVC – Prise en charge de l’AVC en phase aiguë, Traitement antiplaquettaire en phase aiguë
• Lignes directrices relatives au traitement antiplaquettaire de la Société canadienne de cardiologie
• Lignes directrices sur le traitement antithrombotique de l’American College of Chest Physicians
• Ressources relatives aux lignes directrices de la Société canadienne de cardiologie
• Guides cliniques de Thrombose Canada
• Programme d’application des connaissances sur le traitement antiplaquettaire de la Société canadienne de cardiologie (en anglais seulement)  
• CLOT PLUS (CLOT+) est un répertoire continuellement mis à jour des meilleures données probantes actuelles issues de la recherche, à l’appui des prises de décisions cliniques fondées sur des données probantes (en anglais seulement)

Informations destinées au patient

• Cœur + AVC – Liste de vérification après un AVC
• Cœur + AVC – Votre cheminement après un accident vasculaire cérébral 
• Cœur + AVC – Soutien en ligne et par les pair
• Cœur + AVC – Antiplaquettaires
• Thrombose Canada – Informations pour les patients et leur famille

Antiplatelet Therapy for Ischemic Stroke and Transient Ischemic Attack Evidence Table and Reference List

The use of antithrombotic agents in patients who have experienced an ischemic stroke or transient ischemic attack has been shown 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

The benefit of long-term acetylsalicylic acid (ASA) or aspirin use for secondary prevention is well established. Daily, low-dose ASA reduces the risk of vascular events including myocardial infarction (MI), stroke, and vascular death in patients who have experienced a previous vascular event or who are at high risk of vascular disease. The Antithrombotic Trialists’ Collaboration (ATTC, 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 ASA monotherapy was associated with an 11% reduction in the odds a future vascular event (8.2% vs. 9.1%) among patients with a previous stroke or transient ischemic attack. In 65 trials examining ASA monotherapy, the mean percentage odds reduction of any vascular event, across doses ranging from <75 mg to 1,500 mg, was 23%. Treatment with ASA reduced the number of serious vascular events by 36 per 1,000 per year over two years in patients with a previous history of stroke or transient ischemic attack, compared with placebo. In the 2009 update of the ATTC systematic review, which included 16 secondary prevention trials, there was a significantly reduced risk of any subsequent stroke (RR=0.81, 95% CI 0.68-0.96) associated with ASA therapy, although the risk of major gastrointestinal and other extracranial bleeds was significantly increased.

Antiplatelet Therapy Following Stroke

Long-term treatment with both mono and dual antiplatelet therapy has been shown to reduce the risk of recurrent vascular events in persons with previous cardiovascular/cerebrovascular events. Using the results from 6 RCTs (CAPRIE, ESPS-2, MATCH, CHARISMA, ESPRIT, and PRoFESS), Greving et al. (2019) reported the combination of aspirin/dipyridamole significantly reduced the risk of serious vascular events compared with aspirin monotherapy (RR= 0.83; 95% CI, 0.74–0.94), as did clopidogrel monotherapy (RR= 0.88; 95% CI, 0.78–0.98), and aspirin/clopidogrel combination (RR=0.83; 95% CI, 0.71–0.96); however, only the combination of aspirin + dipyridamole significantly reduced the risk of recurrent ischemic stroke (RR=0.86, 95% CI 0.76–0.97). Combining safety and efficacy outcomes, the highest-ranking net clinical benefit outcome (serious vascular events or major bleeding) profile was achieved by clopidogrel and aspirin/dipyridamole combination (RR=0.89; 95% CI 0.82–0.96 and RR=0.87; 95% CI 0.80–0.95, respectively). Yang et al. (2018) also reported dual antiplatelet therapy (vs. monotherapy) significantly reduced the risk of recurrent stroke (RR=0.69, 95% CI 0.61-0.78) and major vascular events (RR= 0.72, 95%CI 0.64 to 0.80), but increased the risk of major bleeding, in a meta-analysis that included the results of 18 RCTs.

Dual vs. Monotherapy with Clopidogrel

The short-term use of the combination of clopidogrel + aspirin vs. aspirin alone, has been shown to reduce the risk of additional ischemic vascular events within 90 days. The Platelet-Oriented Inhibition in New TIA & Minor Ischemic Stroke (POINT) Trial enrolled 4,881 patients with recent (within previous 12 hours) minor stroke or transient ischemic attack (Johnston et al. 2018). Patients were randomized to receive 81 mg aspirin + 75 mg clopidogrel or aspirin + placebo, for 90 days. The risks of ischemic and hemorrhagic stroke were significantly lower in the clopidogrel group (4.6% vs. 6.3%; HR=0.72, 95% CI 0.56–0.92, and 4.8% vs. 6.4%; HR=0.74, 95% CI 0.58–0.94, respectively), although the risk of major hemorrhage was significantly increased (0.9% vs. 0.4%, HR=2.32, 95% CI 1.10–4.87, p= 0.02). The authors estimated that for every 1,000 patients treated with combination therapy for 90 days, 15 ischemic strokes would be prevented but 5 major hemorrhages would result. The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, randomized 5,170 patients with minor ischemic stroke, sustained within the previous 24 hours or high-risk transient ischemic attack, 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 or an MI, stroke or vascular death stroke (8.4% vs. 11.9%, HR=0.69, 95% CI 0.58- 0.82). There was no difference in (any) bleeding events between groups (2.3% vs. 1.6%, p=0.09). The generalizability of the results of this trial have been questioned as the trial was conducted in China, which has a higher incidence of stroke compared with North America. Pan et al. (2019) conducted a patient-level meta-analysis, using the results from the POINT and CHANCE trials. The risks of a major ischemic event, ischemic stroke, disabling or fatal stroke and nondisabling stroke were all reduced significantly with dual antiplatelet therapy, while the risk of hemorrhagic events was not increased significantly. The risk of a major ischemic event associated with dual antiplatelet therapy was reduced significantly from days 0-21(overall), and from days 0-10, but not from days 11-21, or days 22-90. A meta-analysis including the results from 13 RCTs, with a mean duration of follow-up of one-year (Palacio et al. 2015) reported the use of clopidogrel plus aspirin was associated with significantly reduced odds of any stroke compared with aspirin alone (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) after a median of one-year follow-up, while the odds of major hemorrhage were not significantly increased (OR=0.91, 95% CI 0.40-2.07).

Ticagrelor

Although used more frequently to prevent coronary thrombotic events, ticagrelor is another antiplatelet agent that has been shown to reduce the risk of ischemic stroke when used as both a monotherapy (compared with aspirin) and in combination with aspirin. In the SOCRATES Trial, Johnston et al. (2016) included 13,199 patients ≥40 years, who had suffered a minor acute ischemic stroke (NIHSS score of ≤5) or high-risk transient ischemic attack (ABCD2 score of ≥4) or with symptomatic intracranial or extracranial arterial stenosis, to be randomized to receive either ticagrelor (loading dose of 180 mg, followed by 180 mg daily for days 2-90 + aspirin placebo) or aspirin (loading dose of 300 mg, followed by 300 mg daily for days 2-90+ ticagrelor placebo) within 24 hours after symptom onset. Although the p-values were not considered significant on the basis of their statistical plan, by 90 days there were fewer occurrence of both ischemic stroke and all stroke in the ticagrelor group (5.8% vs. 6.7%, HR=0.87, 95% CI 0.76-1.00, and 5.9% vs. 6.8%, HR=0.86, 95% CI 0.75-0.99, respectively). By 90 days, the primary outcome (first occurrence of any event from the composite of stroke, MI, or death) occurred in 6.7% of patients in the ticagrelor group vs. 7.5% in the aspirin group (HR=0.89, 95% CI 0.78-1.01, p=0.007). When combined with 75 to 100 mg of aspirin daily, 90 mg of ticagrelor twice daily, the risk of recurrent stroke or death was significantly reduced in the dual therapy group compared with aspirin alone (5.5% vs. 6.6%, HR=0.83, 95% CI 0.71-0.96, p=0.02) in the THALES trial (Johnston et al. 2020). The risk of ischemic stroke was also significantly lower in the ticagrelor–aspirin group (5.0% vs. 6.3%, HR=0.79, 95% CI 0.63-0.94, p=0.04), although the risk of severe bleeding and intracranial hemorrhage or fatal bleeding were each four times higher in the ticagrelor–aspirin group.

Novel Oral Anticoagulants

While anticoagulants are known to reduce the risk of embolic stroke in patients with atrial fibrillation, Hart et al (2018) hypothesized that they might be more effective than antiplatelet therapy for the prevention of recurrent stroke in patients with recent embolic stroke of undetermined source. In the NAVIGATE ESUS trial, 7,213 patients with an ischemic, non-lacunar stroke of undetermined source were randomized to receive 15 mg rivaroxaban + aspirin placebo or 100 mg of enteric coated aspirin + rivaroxaban placebo. The trial was terminated early due to an excess risk of bleeding among patients in the rivaroxaban group and an absence of benefit. The primary efficacy outcome (ischemic or hemorrhagic stroke or systemic embolism) occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (HR=1.07; 95% CI, 0.87 to 1.33; p=0.52). Similarly, the use of dabigatran did not reduce the risk of recurrent stroke in the RE-SPECT ESUS Trial (Diener et al. 2019). 5,390 patients ≥60 years, with stroke of undetermined source, sustained within the previous 3 months, or with at least one vascular risk factor identified within the previous 6 months, were randomized to receive 150 or 110 mg depending on age and kidney function) dabigatran twice daily or 100 mg plain aspirin once daily. After a median duration of follow-up of 19 months, the risk of recurrent stroke was not reduced significantly in the dabigatran group (4.1% vs. 6.6%, HR=0.85; 95% CI 0.69 to 1.03), nor was the risk of ischemic stroke (4.0% vs. 4.7% per year, HR=0.84, 95% CI 0.68–1.03). Although the risk of major bleeding was not increased significantly with dabigatran, the risk of clinically relevant nonmajor bleeding resulting in hospitalization, was increased (1.6% vs. 0.9% per year, HR= 1.73, 95% CI 1.17–2.54).

Sex and Gender Considerations:

There is no evidence of a differential effect of antiplatelet agents used for secondary stroke in women compared with men. For example, in the Antithrombotic Trialists’ Collaborative (Baigent et al. 2009), using secondary prevention trials, the risk of ischemic stroke was not significantly different among aspirin users (men: RR= 0·73, 95% CI 0·50–1·06 vs. women: RR= 0·91, 95% CI 0·52–1·57). A patient-level network meta-analysis (Greving et al. 2019), examining mono or dual antiplatelet therapy for long-term secondary prevention reported there was no evidence of heterogeneity of treatment effect for sex, or any other prespecified subgroups for the outcome of serious vascular events.