Antiplatelet Therapy

Antiplatelet agents are considered a fundamental component of secondary stroke prevention.⁹⁵  Several clinical trials have shown that antiplatelet medications (such as acetylsalicylic acid) reduce the risk of further vascular events after transient ischemic attack or ischemic stroke (25 percent relative risk reduction).¹³⁸ This effect is modest and is clinically useful because antiplatelet therapy is tolerated by the majority of patients who have had a transient ischemic attack or ischemic stroke. Trials comparing different antiplatelet therapy regimes show quite small absolute differences in efficacy, rendering the options equivocal.

• Stroke prevention clinics to improve secondary stroke prevention (effective, consistent prevention with early recognition of risk factors and timely, targeted interventions).
• Optimization of strategies at the local, regional and provincial levels to prevent the recurrence of stroke.
• Stroke prevention awareness and education about secondary prevention for primary care practitioners and specialists who manage stroke patients during the acute phase and after discharge from acute care.

1. Proportion of acute ischemic stroke and TIA patients who receive acute antiplatelet therapy within the first 48 hours of hospital arrival (core).
2. Proportion of patients with ischemic stroke or transient ischemic attack prescribed antiplatelet therapy on discharge from acute care (core).
3. Proportion of patients with ischemic stroke or transient ischemic attack prescribed antiplatelet therapy on discharge from secondary prevention clinic care (core).  

Measurement Notes 

• Data sources include patient chart, nurses’ notes, physicians’ orders and discharge summary note. Documentation quality may affect ability to accurately monitor this performance measure.
• It may be a challenge to measure compliance and prescribing patterns in primary care.
• Some patients may be on anticoagulants and would therefore be considered exclusions to these measures. See Canadian Stroke Strategy Performance Measurement Manual for additional measures on all antithrombotic prescribing (www.canadianstrokestrategy.ca).
• Reasons potentially eligible patients are not prescribed antiplatelet agents should be included in data collection. This information may contribute to the interpretation of the findings of the performance measures and guide quality improvement initiatives.

• Canadian Cardiovascular Society: http://www.ccs.ca/home/index_e.aspx
• 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.^95-97 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.⁹⁸ 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.⁹⁹ 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.⁹⁹  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.¹⁰⁰  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.¹⁰¹  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.⁹⁶ 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.

In a meta-analysis, 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.¹⁰³  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.¹⁰³

A review by Halkes and colleagues studied five trials of dipyridamole plus ASA versus ASA alone for secondary prevention of stroke or TIA, and included the ESPRIT results.¹⁰⁴  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, ASA dose, type of vessel disease and dipyridamole formulation, nor across baseline risk strata as assessed with two different risk scores. Dipyridamole plus ASA was more effective than ASA alone in preventing recurrent stroke; HR 0.78 (95% CI 0.68 to 0.90). The dose of ASA 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 ASA was left to the discretion of the treating physician, provided it was between 30 and 325 mg daily. The investigators concluded the combination of ASA and dipyridamole is more effective that ASA 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 most recent trial, SPS3, examined the effects of antiplatelet therapy on lacunar strokes that occur as a result of cerebral small vessel disease.¹¹⁰  This double blind randomized trial compared daily clopidogrel to placebo, with both groups also receiving 325 mg of aspirin daily.  The results demonstrated that the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). However, there was a significant difference in the number of major hemorrhagic events, where the rate was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001).

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.¹⁰⁵ 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.¹⁰⁶ 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).¹⁰¹ 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/day) plus low-dose ASA (75 to 162 mg/day) or placebo plus low-dose ASA and followed them for a median of 28 months.¹⁰⁷ 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).¹⁰⁷  Among 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.¹⁰⁸  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.¹⁰⁹

Pediatrics

ASA is frequently used in children for the secondary prevention of recurrent stroke following a transient ischemic attack or stroke event.¹¹¹   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, but it is clear that no treatment is associated with increased risk of recurrent stroke.¹¹²  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.¹¹³

Clopidogrel has been studied as an alternative to ASA in children when ASA is not tolerated or failed in children with arterial ischemic stroke.^{88, 114,115}  Seventeen children were included in the study and started on clopidogrel at 1 mg/kg per day up to a maximum of 75 mg/day.^88,  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 ASA, and the combination of clopidogrel and ASA should be used with caution.

Studies have examined the use of Clopidogrel in children with heart disease for platelet inhibition and reported it safe and efficacious at similar doses reported by Soman et al for stroke patients. In one study of Clopidogrel in 46 children with heart disease, the mean age of first clopidogrel dose was 4.9 +/- 4.1 years.¹¹⁵ The study dosage ranged from 0.1 to 0.7 mg/kg/day clopidogrel. Almost all patients received concomitant ASA therapy.  The primary outcome was thrombolytic events, and after treatment no thrombotic events developed. Hematological abnormalities occurred in one child after one year of therapy and these reversed after cessation of therapy.  Similarly, Li and colleagues (2008) found that clopidogrel 0.20 mg · kg⁻¹ · d⁻¹ in children 0 to 24 months of age achieved a platelet inhibition level similar to that in adults taking 75 mg/d. ¹¹⁶  These studies both concluded Clopidogrel appeared safe and efficacious in children, but stressed the need for randomized controlled research trials to establish dosing and safety in children.