Thérapie antiplaquettaire

Les agents antiplaquettaires sont considérés comme incontournables dans la prévention de l'AVC secondaire (Yip 2011). 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).¹³⁸ Cet effet modeste est utile sur le plan clinique parce que les antiplaquettaires sont bien tolérés par la majorité des patients avec AVC ou AIT. Les essais comparant différents schémas posologiques d’antiplaquettaires concluent à de toutes petites différences en termes d’efficacité absolue; leur choix est par conséquent équivoque.

• Cliniques de prévention de l’AVC 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 des stratégies aux niveaux local, régional et provincial qui ciblent la prévention de l’AVC récidivant
• Programmes de sensibilisation à la prévention de l’AVC et d’éducation sur la prévention secondaire destinés aux fournisseurs de soins primaires et aux spécialistes qui prennent en charge des patients durant la phase aiguë d'un AVC et après le congé des soins aigus

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 (de base)
2. Proportion des patients avec AVC ischémique ou AIT à qui on a prescrit un traitement antiplaquettaire au congé des soins aigus (de base)
3. Proportion des patients avec AVC ischémique ou AIT à qui on a prescrit un traitement antiplaquettaire au congé des soins en clinique de prévention secondaire (de base)

Notes relatives à la mesure des indicateurs

• Sources de données : dossier médical du patient, notes du personnel infirmier, ordonnances des médecins et résumé au 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’adhésion et des habitudes de prescription des ordonnances peut poser des défis.
• 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.strategieavc.ca).
• Les raisons pour lesquelles des antiplaquettaires n’ont pas été prescrits à des patients potentiellement admissibles doivent figurer dans la collecte de données ; ces renseignements peuvent faciliter l’interprétation des résultats de la mesure de l’indicateur de rendement et orienter les initiatives d’amélioration de la qualité des soins.

• Société canadienne de cardiologie
• Chest guidelines

Substantial evidence from randomized trials and meta-analyses supports the use of antithrombotic agents in patients who have experienced an ischemic stroke. The most commonly recommended antiplatelet agents for secondary stroke prevention in North America and Europe are acetylsalicylic acid (ASA) , clopidogrel and the combination of ASA and extended-release dipyridamole.¹³⁹ Although some controversy regarding ASA dosage still exists, most guidelines recommend medium dose ASA (75 to 325 mg/day) as the first choice in secondary prevention of stroke. Other antiplatelet agents are acceptable alternatives. For patients with a stroke due to a cardioembolic source (e.g., atrial fibrillation, mechanical heart valve), warfarin is generally recommended (see recommendation 2.6, “Antithrombotic therapy in atrial fibrillation”) unless contraindicated. Warfarin is not recommended for secondary stroke prevention in patients presumed to have a non-cardioembolic stroke or transient ischemic attack.

Systematic reviews

In a critical review by O’Donnell and colleagues, immediate and long-term ASA therapy was found to reduce the risk of recurrent stroke, myocardial infarction and vascular-related death for patients with ischemic stroke or transient ischemic attack.¹⁴⁰ Oral anticoagulation was not more effective than ASA. In comparison to ASA, long-term clopidogrel reduces the relative risk of stroke, myocardial infarction or vascular death by approximately nine percent. Any benefit of combination antiplatelet therapy with clopidogrel and ASA appears to be offset by an increased incidence of major bleeding complications compared with either agent alone. The combination of ASA and extended- release dipyridamole appeared to reduce the relative odds of stroke, myocardial infarction or vascular death by about 18 percent (OR 0.82, 95% CI 0.74–0.91) compared with ASA alone, without causing more bleeding.¹⁴⁰

Verro and associates recently published a review of randomized controlled trials comparing ASA plus dipyridamole with ASA alone in patients with stroke and transient ischemic attack to determine the efficacy of these agents in preventing recurrent vascular events.¹⁴¹ Separate analyses of the incidence of stroke alone and the composite outcome of stroke, myocardial infarction or vascular death were performed, as well as two a priori subset analyses examining effect size based on trials using (1) exclusively immediate-release and (2) predominantly extended-release dipyridamole. Results indicated a significant reduction in the overall risk ratio in favour of ASA plus dipyridamole for stroke (RR 0.77, 95% CI 0.67–0.89) and for the composite end point (RR 0.85, 95% CI 0.76–0.94). Studies using immediate-release dipyridamole showed a non-statistically significant trend in favour of the combination for stroke (RR 0.83, 95% CI 0.59–1.15) and for the composite outcome (RR 0.95, 95% CI 0.75–1.19). Studies using predominantly extended-release dipyridamole showed a statistically significant difference in favour of the combination for stroke (RR 0.76, 95% CI 0.65–0.89) and for the composite outcome (RR 0.82, 95% CI 0.73–0.92). These findings indicate that ASA in combination with dipyridamole was more effective than ASA alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack.¹⁴¹ The risk reduction was greater and statistically significant for studies using primarily extended-release dipyridamole, which may be a reflection of a true pharmacologic effect or lack of statistical power in studies using immediate-release dipyridamole.

A 2007 review surveyed the clinical trials and guidelines concerning the use of antiplatelet therapy in the prevention of recurrent stroke after transient ischemic attack or ischemic stroke of arterial origin.¹⁴² Meta-analyses of the results from the randomized controlled trials demonstrated that, compared with control, the relative risk reduction for recurrent stroke and other serious vascular events was 13 percent with ASA, 13 percent with dipyridamole (95% CI 4% to 21%; p = 0.046) and 34 percent with combination ASA and dipyridamole. Compared with ASA, the relative risk of recurrent stroke and other serious vascular events was reduced by 7.3 percent with clopidogrel (95% CI –5.7% to 18.7%) and 18 percent with combination ASA and dipyridamole (9% to 26%, p = 0.0003). Long-term treatment with the combination of ASA and clopidogrel was not significantly more effective in preventing serious vascular events than clopidogrel alone, mainly due to an increased frequency of bleeding complications among patients receiving both agents.

An updated Cochrane systematic review assessed the efficacy and safety of dipyridamole relative to control in the secondary prevention of vascular events in patients with vascular disease.¹⁴³ The review included randomized long-term secondary prevention trials with concealed treatment allocation, treatment for more than one month, starting within six months after presentation of an arterial vascular disease. Treatment consisted of dipyridamole with or without other antiplatelet drugs compared with no drug or an antiplatelet drug other than dipyridamole. Twenty-seven trials were included, with 20 242 patients, among whom 1399 vascular deaths and 3090 fatal and nonfatal vascular events occurred during follow-up. Compared with control, dipyridamole had no clear effect on vascular death (RR 1.02, 95% CI 0.90–1.17). This result was not influenced by the dose of dipyridamole or type of presenting vascular disease. In the presence of ASA, dipyridamole appeared to reduce the risk of vascular events compared with control (RR 0.90, 95% CI 0.82–0.97), due to a single large trial (Second European Stroke Prevention Study [ESPS2]) in patients presenting with cerebral ischemia.¹⁴⁴ The authors concluded that for patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of another antiplatelet drug, reduced the risk of vascular death, though it may reduce the risk of further vascular events. However, this benefit was found in only one large trial and only in patients presenting after cerebral ischemia. There was no evidence that dipyridamole alone was more efficacious than ASA.

The Antithrombotic Trialists’ Collaboration produced a meta-analysis of randomized controlled trials for antiplatelet therapy in high risk patients.¹³⁸ The findings indicated that ASA and other forms of antiplatelet drugs reduced the incidence of nonfatal stroke by one-quarter. Absolute reduction in the rates of having a serious vascular event were 36 (standard deviation [SD] 6) per 1000 patients treated for two years among those patients with previous stroke or transient ischemic attack. The authors concluded that the benefits of ASA and other antiplatelet drugs substantially outweigh the absolute risks of major extracranial bleeding.

Hankey and coworkers assessed the effectiveness and safety of thienopyridine derivatives (ticlopidine and clopidogrel) compared with ASA for the prevention of serious vascular events in high-risk patients.¹⁴⁵ Four high-quality and comparable trials, including 22 656 patients at high risk for adverse vascular events, were identified (three compared ASA to ticlopidine and one compared ASA to clopidogrel). The use of a thienopyridine was associated with a marginally significant reduction in the odds of serious vascular event (12.0% v.13%; OR 0.91, 95% CI 0.84–0.98; p = 0.01). There was also a reduction in stroke events in favour of thienopyridines compared with ASA (5.7% v. 6.4%; OR 0.88, 95% CI 0.79–0.98) corresponding to an avoidance of 7 (95% CI 1–13) stroke events per 1000 patients treated for two years. In a subgroup analysis of patients with ischemic stroke or transient ischemic attack, the results were similar to those of all patients combined; however, thienopyridine allocation was associated with a larger absolute reduction in stroke (10.4% v. 12.0%; OR 0.86, 95% CI 0.75–0.97) with an avoidance of 16 (95% CI 3–28) stroke events per 1000 patients treated for two years.¹⁴⁵

A review by Halkes and colleagues studied five trials of dipyridamole plus aspirin versus aspirin alone for secondary prevention of stroke or TIA, and included the ESPRIT results.¹⁴⁶ A total of 7612 patients A total of 7612 patients were included in the analyses (five trials). The trial-adjusted hazard ration (HR) for composite event of vascular death, non-fatal myocardial infarction and non-fatal stroke was 0.82 (95% confidence interval, 0.72 to 0.92). Hazard ratios did not differ in subgroup analyses based on age, sex, qualifying event, hypertension, diabetes, previous stroke, ischemic heart disease, aspirin dose, type of vessel disease and dipyridamole formulation, nor across baseline risk strata as assessed with two different risk scores. Dipyridamole plus aspirin was more effective than ASA alone in preventing recurrent stroke; HR 0.78 (95% CI

0.68 to 0.90). The dose of aspirin was fixed in four trials: 25 mg twice daily, 300 mg three times daily, 325 mg three times daily or 330mg three times daily. IN ESPRIT, the dose of aspirin was left to the discretion of the treating physician, provided it was between 30 and 325 mg daily. The investigators concluded the combination of aspirin and dipyridamole is more effective that aspirin alone in patients with TIA or ischemic stroke of presumed arterial origin in the secondary prevention of stroke and other vascular events. The superiority was found in all subgroups and was independent of baseline risk.

Clinical trials

The Prevention Regimen For Effectively avoiding Second Stroke (PRoFESS) trial, randomized, double-blind study, investigated the effects of ASA plus extended-release dipyridamole versus clopidogrel on the prevention of vascular events in patients who had a transient ischemic attack or ischemic stroke within the preceding 120 days.¹⁴⁷ Patients participating in the trial (n = 20 332 across 35 countries) were followed for a period of four years. Stroke recurrence rates were similar in both arms of the trial (9.0 percent among patients assigned to receive ASA plus extended-release dipyridamole and 8.8 percent among patients assigned to receive clopidogrel; HR 1.01, 95% CI 0.92–1.11). Nor was there a significant difference in the composite outcome of stroke, myocardial infarction or vascular death. The trial did not meet its primary end point of noninferiority for ASA plus extended-release dipyridamole versus clopidogrel.

The European/Australian Stroke Prevention Reversible Ischemia Trial (ESPRIT) group conducted a randomized controlled trial in which patients were assigned to ASA (30–325 mg daily) with (n = 1363) or without (n = 1376) dipyridamole (200 mg twice daily) within six months of a transient ischemic attack or minor stroke of presumed arterial origin.¹⁴⁸ The primary outcome was the composite of death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction or major bleeding complication, whichever happened first. Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. Mean follow-up was 3.5 years (SD 2.0). Median ASA dose was 75 mg in both treatment groups (range 30–325); extended-release dipyridamole was used by 83 percent (n = 1131) of the patients on the combination regimen. Primary outcome events arose in 173 (13%) patients on ASA and dipyridamole and in 216 (16%) on ASA alone (HR 0.80, 95% CI 0.66–0.98; absolute risk reduction 1.0% per year, 95% CI 0.1%–1.8%). Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke or myocardial infarction of 0.82 (95% CI 0.74–0.91).¹⁴⁸ Patients on ASA and dipyridamole discontinued trial medication more often than those on ASA alone (470 v. 184), mainly because of headache. Expressed differently, ESPRIT showed that 104 patients would need to be treated with the combination regimen for 1 year to prevent 1 additional vascular death, nonfatal stroke or nonfatal myocardial infarction.

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 per day) plus low-dose ASA (75 to 162 mg per day) or placebo plus low-dose ASA and followed them for a median of 28 months.¹⁴⁹ The primary efficacy end point, a composite of nonfatal stroke, nonfatal myocardial infarction or vascular death, was reached by 6.8 percent of patients assigned to receive clopidogrel plus ASA and 7.3 percent of those assigned to receive placebo plus ASA (RR 0.93, 95% CI 0.83–1.05; p = 0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (RR 0.92. 95% CI 0.86–0.995; p = 0.04). Severe bleeding occurred in 1.7 percent of patients assigned to receive clopidogrel plus ASA and 1.3% percent of those assigned to receive placebo plus ASA (RR 1.25, 95% CI 0.97–1.61; p = 0.09).¹⁴⁹Among patients with multiple risk factors, the primary end point was reached by 6.6% of the clopidogrel plus ASA group and 5.5 percent of the placebo plus ASA group (RR 1.2, 95% CI 0.91–1.59; p = 0.20). Death from cardiovascular causes occurred in 3.9% of patients assigned to receive clopidogrel plus ASA and 2.2 percent of those assigned to receive placebo plus ASA (p = 0.01). In the subgroup with clinically evident atherothrombosis, a marginally significant reduction in the primary end point of 6.9 percent with clopidogrel and 7.9 percent with placebo was indicated (RR 0.88, 95% CI 0.77–0.998; p = 0.046). The investigators concluded that there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors; however, overall, clopidogrel plus ASA was not significantly more effective than ASA alone in reducing the rate of myocardial infarction, stroke or vascular death.

The Management of Atherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic stroke (MATCH) trial was a randomized, double-blind, placebo-controlled comparison of ASA (75 mg/day)

with placebo in 7599 high-risk patients with recent ischemic stroke or transient ischemic attack and at least 1 additional vascular risk factor who were already receiving clopidogrel 75 mg/day.¹⁵⁰ Duration of treatment and follow-up was 18 months. The primary end point was a composite of ischemic stroke, myocardial infarction, vascular death or rehospitalization for acute ischemia (including rehospitalization for transient ischemic attack, angina pectoris or worsening of peripheral arterial disease). The primary end point was reached by 596 (15.7%) of the patients assigned to receive ASA and clopidogrel, and 636 (16.7%) of the patients assigned to receive placebo plus clopidogrel (relative risk reduction 6.4%, 95% CI –4.6% to 16.3%; absolute risk reduction 1%, 95% CI –0.6% to 2.7%). Life-threatening bleeding was higher in the group assigned to receive ASA and clopidogrel (2.6%) than in the group assigned to receive placebo plus clopidogrel (1.3%) (absolute risk increase 1.3%, 95% CI 0.6% to 1.9%). Major bleeding was also increased in the group assigned to receive ASA and clopidogrel. There was no difference in mortality between the 2 groups. The investigators concluded that adding ASA to clopidogrel in high-risk patients with recent ischemic stroke or transient ischemic attack was associated with a nonsignificant reduction in major vascular events and an increase in the risk of life-threatening or major bleeding after 18 months of follow-up.

The Clopidogrel versus ASA in Patients at Risk of Ischemic Events (CAPRIE) trial randomized 19 185 symptomatic patients (one-third had experienced a previous stroke, one-third had a previous myocardial infarction, and one-third had peripheral vascular disease) to clopidogrel (75 mg) or ASA (325 mg).¹⁵¹ An 8.7 percent (95% CI 0.3%–16.5%; p = 0.043) reduction in the primary end point of ischemic stroke, myocardial infarction or vascular death in favour of clopidogrel was reported. Among the patients whose qualifying event was a stroke, the number needed to treat with clopidogrel instead of ASA to prevent a recurrent ischemic event was about 180 per year.¹⁵²

Paediatrics

ASA is frequently used in children for the secondary prevention of recurrent stroke following a transient ischemic attack or stroke event. In adults, it has been demonstrated that treatment with ASA can reduce the risk of recurrent stroke. Data on the efficacy and optimal dosage of ASA for paediatric stroke patients are not yet available,⁴¹ but it is clear that no treatment is associated with increased risk of recurrent stroke.¹⁵³ ASA use has been recommended as a reasonable option for secondary prevention of arterial ischemic stroke for children not at high risk of recurrent embolism or a hypercoaguable disorder.¹²

Clopidogrel has been studied as an alternative to aspirin in children when aspirin is not tolerated or failed in children with arterial ischemic stroke.¹³⁷ Seventeen children were included in the study and started on clopidogrel at 1 mg/kg per day up to a maximum of 75 mg per day. Of these, eight were on clopidogrel alone and nine in combination with ASA. Two patients developed significant intracranial hemorrhage while on the combination of clopidogrel and ASA – one has recent surgery and the other had hypertension prior to the start of therapy, as well as marked cerebral atrophy. This small initial investigation concluded that clopidogrel appears to be a reasonable option in children who cannot tolerate aspirin, and the combination of clopidogrel and aspirin should be used with caution.