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Acute Stroke Management

6. Acute Antiplatelet Therapy

Section Six Recommendations for Acute Antiplatelet Therapy
  1. All acute stroke patients not already on an antiplatelet agent and not receiving alteplase therapy should be given at least 160 mg of acetylsalicylic acid (ASA) immediately as a one-time loading dose after brain imaging has excluded intracranial hemorrhage and after dysphagia screening has been performed and passed. [Evidence Level A].
    1. Acetylsalicylic acid (81 to 325 mg daily) should then be continued indefinitely or until an alternative antithrombotic regime is started [Evidence Level A]. Refer to Canadian Stroke Best Practice Recommendations Prevention of Stroke Module Sections 6 and 7 for additional information on antithrombotic therapy
  2. In very high risk TIA patients (refer to Box 6A below and Section 2.1 for determination of very high risk patients or per POINT trial criteria of ABCD2 score > 4) or minor stroke of non cardioembolic origin (NIHSS 0-3), a combination of clopidogrel and acetylsalicylic acid should be given for a duration of 21 to 30 days followed by antiplatelet monotherapy (such as acetylsalicylic acid or clopidogrel alone) [Evidence Level A]. A minimal loading dose of 300 mg Clopidogrel (based on dose in CHANCE) up to 600mg (based on dose used in POINT) and 160 mg of acetylsalicylic acid should be given at the start of treatment [Evidence Level A]. 9, 57
    1. Dual antiplatelet therapy should be started as soon as possible after brain imaging, within 24 hours of symptom onset, and ideally within 12 hours.
    2. Dual antiplatelet therapy should be started prior to discharge from the Emergency Department.
    3. Patients should be counseled that dual antiplatelet therapy with aspirin and clopidogrel should continue for only 21-30 days. Patients should resume monotherapy after completion of dual therapy, and continue monotherapy indefinitely.
  3. In patients treated with tissue plasminogen activator (alteplase), initiation of antiplatelet agents should be delayed until after the 24-hour post-thrombolysis scan has excluded intracranial hemorrhage [Evidence Level B].
  4. In dysphagic patients, acetylsalicylic acid (80 mg daily) and clopidogrel (75 mg daily) may be given by enteral tube or acetylsalicylic acid by rectal suppository (325 mg daily) [Evidence Level A].
  5. In pediatric patients, initial treatment with anticoagulation (heparin) or aspirin at established pediatric dosing should be considered and continued until cervical artery dissection and intracardiac thrombus is excluded. If neither is present, switch to acute aspirin therapy at dose of 1-5 mg/kg [Evidence Level B].

Refer to Canadian Stroke Best Practice Recommendations Secondary Prevention of Stroke module sections 6 and 7 for additional information on use of antithrombotic agents beyond the acute period.

Clinical Considerations:

  1. Patients with very high risk TIA or minor ischemic stroke caused by high-grade carotid stenosis who are candidates for urgent carotid endarterectomy or carotid stenting, should be reviewed with the interventionalist or surgeon to determine the appropriate timing and selection of antiplatelet agent(s). In some circumstances it may be appropriate to use aspirin monotherapy rather than dual antiplatelet therapy if carotid endarterectomy is planned urgently, to reduce peri-operative bleeding risk.
  2. For patients on dual antiplatelet therapy, GI protection may be considered in patients at higher risk of GI bleeding [In POINT (90 day study) extracranial bleeding events were 0.9% in the dual antiplatelet therapy group and 0.4% in the monotherapy group; in CHANCE (21 day study) extracranial bleeding events were 0.3% in the dual antiplatelet therapy group and 0.3% in the monotherapy group.]

Box 6A: VERY HIGH Risk for Recurrent Stroke

The recommendations for this module have been published in International Journal of Stroke by SAGE Publications Ltd. Copyright © 2018 World Stroke Organization.

Rationale +-

Acute-phase aspirin therapy reduces the risk of early recurrent ischemic stroke. Long-term aspirin therapy reduces the risk of ischemic stroke, myocardial infarction, and vascular death. There is a paucity of data from randomized controlled trials to support the use of other antiplatelet regimes in acute stroke patients. In clinical trials for alteplase, antithrombotic drugs (including aspirin) were avoided until after the 24-hour post-thrombolysis scan had excluded intracranial hemorrhage.

System Implications +-
  1. Development and dissemination of protocols and standing order sets to guide initial management of ischemic stroke and transient ischemic attack patients
  2. Pediatric awareness campaigns and education to healthcare professionals to optimize recognition of stroke and management.
Performance Measures +-
  1. Proportion of ischemic stroke or TIA patients who receive acute aspirin therapy within the first 48 hours following symptom onset (core).
  2. Median time from stroke patient arrival to hospital to administration of first dose of aspirin in hospital.

Measurement Notes

  1. Time interval measurements should be taken from the time the patient is triaged or registered at the hospital (whichever time comes first) until the time the first dose is administered.
  2. This indicator focuses on aspirin. Some centres may include other antiplatelet medications, such as clopidogrel or ASA combined with extended release dipyridamole. In cases where another agent is used instead of aspirin in the first 48 hours, this should be noted in the indicator definition.
  3. Possible data sources include history and physical, physician’s admission notes, nurses’ admission notes, medication record.
Summary of the Evidence +-

Evidence Table and Reference List

Aspirin therapy, provided acutely following ischemic stroke, is known to reduce the risk of recurrent (ischemic) stroke.  In an updated Cochrane review, Sandercock et al. (2014) identified 8 RCTs (n=41,483 patients) that compared a single oral antiplatelet agent (aspirin, n=3 or ticlopidine, n=2) or a combination of antiplatelet agents (aspirin + dipyridamole and/or heparin, n=2) with control (placebo or no treatment). In 8/10 trials, therapy was initiated within one week following stroke. The dose of aspirin ranged from 160-325 mg/day and treatment duration ranged from 5 days to 3 months following stroke. Two large trials testing aspirin, started within 48 hours of stroke onset, contributed 98% of the data (CAST 1997, IST 1997). Antiplatelet therapy was associated with a significant reduction in the odds of being dead or dependent at final follow-up (OR= 0.95, 95% CI 0.91 to 0.99, p= 0.01). Treatment was also associated with a marginally significant reduction in death during treatment (OR= 0.92, 95% CI 0.85 to 1.00, p=0.05 and a significant reduction in the odds of death at a final follow-up (OR=0.92, 95% CI 0.87 to 0.99, p=0.01).  Although antiplatelet therapy was associated with a significant increase in the odds of intracerebral hemorrhage (OR=1.23, 95% CI 1.00 to 1.50, p=0.04), a net reduction was reported in the odds of any stroke recurrence (i.e., ischemic or hemorrhagic; OR=0.88, 95% CI 0.80 to 0.97).  For every 1,000 people treated with aspirin, 13 fewer people would avoid death or dependency, 9 fewer would avoid death and 7 fewer would avoid a recurrent stroke. The results from a patient-level meta-analysis using 3 RCTs, (Rothwell et al. 2016) suggest that the greatest reduction in early stroke recurrence associated with aspirin monotherapy is among patients presenting with mild or moderately disabling stroke. Aspirin therapy was not associated with a significant reduction in stroke recurrence among those with a severe stroke. 

There is some evidence to suggest that dual antiplatelet therapy, provided in the early post-stroke period may help to reduce the risk of recurrent stroke. Greengage et al. (2012) included the results from 12 trials assessing various combinations and doses of other antiplatelet agents, in addition to aspirin. Based on the results from all trials, dual therapy was associated with significantly reduced risks of recurrent stroke (RR=0.67, 95% CI 0.49-0.93, p=0.02), composite of stroke, MI and vascular death (RR= 0.75; 95% CI, 0.56 – 0.99, p=0.04), without significant increases in ICH or major bleeding events. In contrast, the results of the TARDIS trial (Bath et al. 2017) suggest that triple antiplatelet therapy with aspirin, dipyridamole and clopidogrel, does not significantly reduce the risk of recurrent stroke, but does increase the risk of bleeding events. 

Clopidogrel is indicated for acute management of ischemic stroke in patients who are not tolerant of aspirin. Two major trials, published within the previous 5 years, both with short-term outcomes, were positive. The most recent one, the Platelet-Oriented Inhibition in New TIA & Minor Ischemic Stroke (POINT) Trial (Johnston et al. 2018), enrolled 4,881 patients with recent (within previous 12 hours) minor stroke or TIA from centres located mainly in the United States. Patients were randomized to receive 81 mg aspirin + 75 mg clopidogrel or aspirin + placebo, for 90 days. The risk of ischemic stroke was significantly lower in the clopidogrel group (4.6% vs. 6.3%; HR=0.72, 95% CI 0.56–0.92, p= 0.01), 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 clopidogrel plus aspirin for 90 days, 15 ischemic strokes would be prevented but 5 major hemorrhages would result. Another positive trial was the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, in which investigators randomized 5,170 patients from China with recent minor ischemic stroke (within previous 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). In the Fast Assessment of Stroke and TIA to prevent Stroke Recurrence (FASTER) trial (Kennedy et al. 2007), randomized 392 patients presenting with minor stroke or TIA to receive clopidogrel or placebo and simvastatin or placebo within 24 hours of the qualifying event. In the antiplatelet arm of the trial, there were non-significant reductions in the risks of recurrent stroke (7.1% vs. 10.8%, RR=0.7, 95% CI 0.3-1.2, p=0.19) and the composite secondary outcome, which included myocardial infarction and death, associated with clopidogrel use. Clopidogrel use was associated with a significant 3% increase in risk (p=0.03) for symptomatic bleeding events.

The addition of dipyridamole to both aspirin and clopidogrel (i.e., triple antiplatelet therapy) to prevent recurrent events within 90 days was found to be associated with increased bleeding events in the TRADIS trial (Bath et al. 2018), compared with standard antiplatelet therapy using one or two agents. There was no significant difference between groups in the incidence or severity of stroke or TIA. The trial was stopped prematurely due to futility and safety concerns.

After thrombolysis, a portion of patients may develop reocclusion, which has been attributed to increased platelet aggregation. Therefore, antiplatelet therapy early after alteplase was thought to potentially reduce the risk of reocclusion and thereby improve functional outcome. However, the results from The Antiplatelet Therapy in Combination with rt-PA Thrombolysis in Ischemic Stroke (ARTIS) Trial suggest that treatment may be associated with harm. Zinkstok & Roos (2012) randomized 640 patients to receive 300 mg of aspirin intravenously within 90 minutes of alteplase treatment or standard treatment (no aspirin).  At the three-month follow-up, although there was no difference between groups in the odds of a good outcome, defined as mRS score of 0-2 (54% vs. 57.2%, OR=0.91, 95% CI 0.66 to 1.26), the risk of symptomatic ICH was significantly higher among patients in the early aspirin group (RR=2.78, 95% CI 1.01 to 7.63, p=0.04).

Controversy exists regarding the use of antiplatelets in the hyperacute management of pediatric patients following stroke. The Royal College of Physicians and the American Heart Association pediatric stroke guidelines both recommend the use of aspirin unless there is a known dissection or cardiac clot, in which case low molecular weight heparin is recommend (Paediatric Stroke Working Group, 2004; Roach et al. 2008). Conversely, the American College of Chest Physicians guidelines (Monagle et al. 2012) suggests supportive care over anticoagulation or aspirin therapy in the absence of a documented, ongoing cardioembolic source.  For neonates with a first ischemic stroke with a documented cardioembolic source, anticoagulation with UFH or LMWH is recommended.

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