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Antiplatelet Therapy in Ischemic Stroke and TIA

5th Edition
2014 UPDATE
December 2014

The Canadian Stroke Best Practice Recommendations for the Secondary Prevention of Stroke, 5th Edition 2014 module is published in the International Journal of Stroke (IJS) (Online Open‑Access available December 2014; Printed Journal scheduled for April 2015).

To access the specific recommendations for Antiplatelet Therapy in Ischemic Stroke and TIA and all other sections of the Secondary Prevention of Stroke module, please click on this URL which will take you to the recommendations online in the IJS:  http://onlinelibrary.wiley.com/doi/10.1111/ijs.12439/full. For the French version of these recommendations, open the appendix at this link : http://onlinelibrary.wiley.com/store/10.1111/ijs.12439/asset/supinfo/ijs12439-sup-0001-si.pdf?v=1&s=b0ed4fff1d7fc435cf4e2a83ccbcbffbdad767de.

All other supporting information, including performance measures, implementation resources, evidence summaries and references, remain available through www.strokebestpractices.ca, and not through the IJS.  Please click on the appropriate sections below for this additional content.

Rationale

Antiplatelet agents are considered a fundamental component of secondary stroke prevention. 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). 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.

System Implications
  • Stroke prevention clinics to improve secondary stroke prevention (effective, consistent prevention with early recognition of risk factors and timely, targeted interventions).
  • Optimization of comprehensive 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.
Performance Measures
  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.
Implementation Resources and Knowledge Transfer Tools
Summary of the Evidence, Evidence Tables and References

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 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, the mean percentage odds reduction of any vascular event, across doses ranging from <75 mg to 1,500 mg, were 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).

Dual vs. Monotherapy with Clopidogrel
Several large clinical trials have examined the combination of clopidogrel + aspirin vs. aspirin alone. Of these, the majority failed to demonstrate a significant reduction in risk of recurrent stroke among patients who had already sustained a minor stroke or TIA. 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 (RR=0.99, 95% CI 0.86-1.14, p=0.90), death from cardiovascular causes (RR=1.04, 95% CI 0.87-1.25, p=0.68) and non-fatal MI (0.94, 95% CI 0.75-1.18, p=0.59) 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 was associated with an increased risk of all-cause mortality. In a subgroup analysis including patients who were on aspirin therapy at the time of the qualifying stroke, 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) 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 single, large trial has examined the treatment contrast of clopidogrel + aspirin vs. clopidogrel alone (Deiner et al. 2004). In the Management of Atherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic stroke (MATCH) trial 7,599 high-risk patients with recent ischemic stroke or transient ischemic attack and at least 1 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 non significant reduction in major vascular events and a significant increase in the risk of life-threatening or major bleeding.

Dual vs. Monotherapy with Dipyridamole
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 relative the superiority of two drug treatment approaches for the prevention of future vascular events (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).

Pediatrics
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 (Roach et al. 2008). Clopidogrel has not been well studied as an alternative in children who do not tolerate or fail on ASA therapy with arterial ischemic stroke. In one small study including 17 children aged 1 to 17 years diagnosed with ischemic stroke, a dose of clopidogrel at 1 mg/kg per day up to a maximum of 75 mg was found to be relatively well tolerated (Soman et al. 2006). Eight children received clopidogrel only and 5 received combination therapy with ASA. Two patients developed significant intracranial hemorrhage while on the combination of clopidogrel and ASA, of whom one had recent surgery and the other had hypertension prior to the start of therapy, as well as marked cerebral atrophy. The authors concluded that clopidogrel appears to be a reasonable option in children who cannot tolerate ASA, but noted the combination of clopidogrel and ASA should be used with caution. Li et al. (2008) reported that a clopidogrel dose of 0.20 mg/kg/day in children 0 to 24 months of age achieved a platelet inhibition level similar to that in adults taking 75 mg/d. Further study using controlled trials are required to establish safe and effective dosing in children.