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Secondary Prevention Of Stroke

1. Initial Risk Stratification and Management of Nondisabling Stroke and TIA

2017 UPDATE October 2017


Note: These recommendations (Section 1) pertain to patients with TIA or subacute, nondisabling ischemic stroke who are not candidates for hyperacute thrombolysis treatment with intravenous alteplase (tPA) or endovascular thrombectomy. For patients with suspected acute stroke that warrant hyperacute investigations to determine eligibility for thrombolysis/endovascular thrombectomy, refer to Hyperacute Stroke Care recommendations).

1.0 Stroke and TIA

1.0 Patients with stroke and TIA who present to an ambulatory setting (such as primary care) or a hospital should undergo clinical evaluation by a healthcare professional with expertise in stroke care to determine risk for recurrent stroke and initiate appropriate investigations and management strategies.

1.1 Timing of Initial Assessment

(Please refer to Table Three below for summary of Stroke Risk Levels and Actions)

1.1.1 VERY HIGH Risk for Recurrent Stroke (Symptom onset within last 48 Hours)

  1. Patients who present within 48 hours of a suspected transient ischemic attack or nondisabling ischemic stroke with the following symptoms are considered at highest risk of first or recurrent stroke:
    1. transient, fluctuating or persistent unilateral weakness (face, arm and/or leg) [Evidence Level B];
    2. transient, fluctuating or persistent speech disturbance/aphasia [Evidence Level B];
    3. fluctuating or persistent symptoms without motor weakness or speech disturbance (eg. hemibody sensory symptoms, monocular vision loss, hemifield vision loss, +/- other symptoms suggestive of posterior circulation stroke such as binocular diplopia, dysarthria [Evidence Level B].
  2. Patients identified as highest risk should be immediately sent to an emergency department with capacity for advanced stroke care (such as brain imaging on site, and ideally access to acute stroke treatments) [Evidence Level C] Refer to Section 1.2 for more information on investigations.
  3. Urgent brain imaging (CT or MRI) and non-invasive vascular imaging (CTA or MRA from aortic arch to vertex) should be completed as soon as possible within 24 hours [Evidence Level B]. Refer to Section 1.2 for more information on investigations.
  4. An electrocardiogram should be completed without delay [Evidence Level B].

1.1.2 HIGH Risk for Recurrent Stroke (Symptom onset between 48 Hours and 2 weeks)

  1. Patients who present between 48 hours and 2 weeks from onset of a suspected transient ischemic attack or nondisabling ischemic stroke with symptoms of transient, fluctuating or persistent unilateral weakness (face, arm and/or leg), or speech disturbance/aphasia are considered at higher risk for first or recurrent stroke [Evidence Level B].
  2. These patients should receive a comprehensive clinical evaluation and investigations by a healthcare professional with stroke expertise as soon as possible [Evidence Level B], ideally initiated within 24 hours of first contact with the healthcare system [Evidence Level C]. Refer to Section 1.2 for more information on investigations.

1.1.3 MODERATE (INCREASED) Risk for Recurrent Stroke (Symptom onset between 48 Hours and 2 weeks)

  1. Patients who present between 48 hours and 2 weeks of a suspected transient ischemic attack or nondisabling ischemic stroke with transient, fluctuating or persistent symptoms without unilateral motor weakness or speech disturbance (e.g. withhemibody sensory symptoms, monocular vision loss, binocular diplopia, hemifield vision loss, or ataxia) may be considered at increased risk of recurrent stroke [Evidence Level C].
  2. These patients should receive a comprehensive clinical evaluation and investigations by a healthcare professional with stroke expertise as soon as possible [Evidence Level B], ideally within 2 weeks of first contact with the healthcare system [Evidence Level C]. Refer to Section 1.2 for more information on investigations.

1.1.4 LOWER Risk for Recurrent Stroke (Time lapse since symptom onset greater than 2 weeks)

  1. Patients presenting more than 2 weeks following a suspected transient ischemic attack or nondisabling ischemic stroke, may be considered as being less urgent, and should be seen by a neurologist or stroke specialist for evaluation, ideally within one month of symptom onset [Evidence Level C]. Refer to Section 1.2 for more information on investigations.
1.2 Diagnostic Investigations

1.2.1 Initial Assessment:

  1. Patients presenting with suspected acute or recent transient ischemic attack or nondisabling ischemic stroke should undergo an initial assessment that includes brain imaging, non-invasive vascular imaging (including carotid imaging),12-lead ECG, and laboratory investigations.
    1. Brain imaging (CT or MRI) and non-invasive vascular imaging (CTA or MRA from aortic arch to vertex) should be completed within time frames based on triage category above [Evidence Level B]. Refer to Table Three.
    2. CT angiography including extracranial and intracranial vasculature from aortic arch to vertex, which can be performed at the time of initial brain CT, is recommended as an ideal way to assess both the extracranial and intracranial circulation [Evidence Level B].
    3. Vascular imaging is recommended to identify significant symptomatic extracranial carotid artery stenosis for which patients should be referred for possible carotid revascularization [Evidence Level A].
    4. Carotid ultrasound (for extracranial vascular imaging) and MR angiography are acceptable alternatives to CTA, and selection should be based on immediate availability, and patient characteristics [Evidence level C].
  2. The following laboratory investigations should be routinely considered for patients with transient ischemic attack or nondisabling ischemic stroke as part of the initial evaluation:
    1. Initial bloodwork: haematology (complete blood count), electrolytes, coagulation (aPTT, INR), renal function (creatinine, e-glomerular filtration rate), random glucose or hemoglobin A1c, and troponin [Evidence Level C]. Refer to Table Four for full list of recommended lab tests.
    2. Subsequent laboratory tests may be considered during patient encounter or as an outpatient, including a lipid profile (fasting or non-fasting); and, screening for diabetes with either a fasting plasma glucose, or 2-hour plasma glucose, or glycated hemoglobin (A1C), or 75 g oral glucose tolerance test [Evidence Level C]. Refer to Diabetes Canada Guidelines for further information (Link)
  3. Patients with suspected transient ischemic attack or ischemic stroke should have a 12-lead ECG to assess cardiac rhythm and identify atrial fibrillation or flutter or evidence of structural heart disease (e.g. myocardial infarction, left ventricular hypertrophy) [Evidence Level B].
  4. For patients being investigated for an acute embolic ischemic stroke or TIA, ECG monitoring for more than 24 hours is recommended as part of the initial stroke work-up to detect paroxysmal atrial fibrillation in patients who would be potential candidates for anticoagulant therapy [Evidence Level A].

Clinical Considerations:

  1. MRI is superior to CT scan in terms of diagnostic sensitivity for transient ischemic attack, and may provide additional information that could guide diagnosis, prognosis, and management decision-making. Decisions regarding MRI scanning should be based on MRI access, availability and timing of appointments.

1.2.2 Additional Investigations for Embolic Stroke of UndeterminedSource (ESUS)

  1. For patients being investigated for an acute embolic ischemic stroke or TIA of undetermined source whose initial short-term ECG monitoring does not reveal atrial fibrillation but a cardioembolic mechanism is suspected, prolonged ECG monitoring for at least 2 weeks is recommended to improve detection of paroxysmal atrial fibrillation in selected patients aged ≥ 55 years who are not already receiving anticoagulant therapy but would be potential anticoagulant candidates [Evidence Level A]. Refer to the Canadian Cardiovascular Society 2016 Atrial Fibrillation Guideline for additional information. Refer to Section 7 in this module on Management of Atrial Fibrillation in Stroke for additional information.
  2. Echocardiography should be considered in cases where a stroke mechanism has not been identified [Evidence Level C].
1.3 Functional Assessment
  1. Selected patients with transient ischemic attack or ischemic stroke should be assessed for neurological impairments and functional limitations when appropriate (e.g., cognitive evaluation, screening for depression, screening of fitness to drive, need for potential rehabilitation therapy, and assistance with activities of daily living), especially for patients who are not admitted to hospital [Evidence Level B]. Refer to Rehabilitation Module Recommendations 5.1 and 5.6 for additional information.
  2. Patients found to have any neurological impairments and functional limitations should be referred to the appropriate rehabilitation specialist for in-depth assessment and management [Evidence Level C].

The recommendations for this module have been published in International Journal of Stroke by SAGE Publications Ltd. Copyright © 2017 World Stroke Organization.

Rationale +-

The goal of outpatient management of transient ischemic attack and non-disabling ischemic stroke is rapid assessment and management to reduce the risk of a recurrent, possibly more serious, event.

There is clear evidence that transient ischemic attacks or minor strokes are unstable conditions that warn of high future risk of stroke, other vascular events, or death. The risk of recurrent stroke after a transient ischemic attack has been reported as 12 to 20 percent within 90 days, and the risk is “front-loaded”, with half of the strokes occurring in the first two days following initial symptom onset. The seven-day risk of stroke following a transient ischemic attack can be as high as 36 percent in patients with multiple risk factors. Timely initiation of secondary prevention medical therapy and carotid endarterectomy has been shown to significantly reduce the risk of major stroke after an initial transient ischemic attack or non-disabling stroke. A recent study by the TIARegistry.Org group reported updated rates that were less than half that expected from historical cohorts and could be explained by better and faster implementation of secondary stroke prevention strategies in this cohort through rapid-access TIA clinics. (N Engl J Med 2016;374:1533-42)

System Implications +-
  1. Education for the public and healthcare providers (primary, acute and specialists) about the urgency of assessment and management of transient ischemic attack or non-disabling ischemic stroke is critical to reduce the risk of recurrent, potentially more serious events. Patients and families will also require ongoing education and support related to prevention and management of stroke and its associated risk factors.
  2. Education and training for physicians who work in primary, secondary, and tertiary care settings, to enable the management of patients with transient ischemic attack or non-disabling ischemic stroke in a timely manner.
  3. Processes, protocols and infrastructure in place to enable rapid access to diagnostic tests and expertise for patients with transient ischemic attack or minor stroke in community healthcare settings and acute healthcare facilities.
  4. Well-established and accessible stroke prevention clinics, or broader vascular prevention programs available in all communities through traditional or technological means. Promotion of programs with healthcare practitioners. These resources should be listed, easily accessible to primary care physicians and healthcare providers, and updated annually.
  5. Monitoring, assessment and improvement of program regarding uptake, adherence and quality of stroke prevention programs to ensure patients can access effective services. Consideration should be give to community and individual barriers as well as motivators and enablers.
  6. Any suspicion of ischemic stroke in a child warrants an emergent consult or assessment in a pediatric emergency department. All hospitals should have a referral process established with the closest specialized pediatric facility.
Performance Measures +-
  1. Proportion of acute stroke and TIA patients who are discharged alive from an emergency department or an inpatient stay and then readmitted to hospital for any cause within 7 days of index acute stroke discharge (KQI).
  2. Proportion of patients with TIA or non-disabling stroke who are investigated and discharged from the emergency department who are referred to organized secondary stroke prevention services at discharge. (KQI)
  3. Time from first encounter with medical care (primary care or emergency department) to assessment by a stroke expert (in clinic or other setting).
  4. Proportion of patients with motor and speech TIAs who have CT head and CTA completed (or other vascular imaging) within 24 hours of presentation.
  5. Time from first encounter with medical care to brain imaging (CT/MRI); vascular imaging (Doppler of cervical arteries, CT or MR angiography); and electrocardiogram.
  6. Developmental KQI: Proportion of HIGHEST risk TIA and non-disabling stroke patients who are investigated and managed within 24 hours in the ED or referred to organized secondary stroke prevention services (KQI)

Measurement Notes

  • Data access and quality with respect to timing of first encounter and referral dates and times.
  • Primary care data from physician billing. This should rely on International Classification of Diseases (ICD) codes and not on physician descriptions of diagnoses, as these may be less accurate.
  • Measures from other prevention recommendations in this document also apply applicable to this recommendation but are not repeated here.
Summary of the Evidence 2017 +-

Initial Triage and Evaluation Evidence Tables and Reference List

Patients who present with TIA or minor stroke are at increased risk of recurrent stroke, particularly within the first week following the initial event. A systematic review conducted by Giles & Rothwell (2007) pooled the results from 18 studies, consisting of 10,126 patients with TIA. The risk of stroke at days 2 and 7 was 3.1% 5.2%, respectively.  More recently, Perry et al. (2014) examined stroke risk in 3,906 patients with TIAs admitted to 8 emergency departments over a 5-year period. In this cohort, 86 patients (2.2%) developed subsequent stroke within 7 days, and 132 (3.4%) at 90 days. Purroy et al. (2012) reported similar recurrent stroke in 2.6% of patients within 7 days and 3.9% within 90 days among 1,137 patients admitted to 30 centers in Spain, presenting with TIA. Following the first 30 days, the risk of recurrent stroke appears to decline. Mohan et al. (2011) included the results from 13 studies of patients recovering from first-ever stroke who were participants of hospital and community-based stroke registries. The cumulative risks of stroke recurrence: over time were 3.1% at 30 days; 11.1% at one year; 26.4% at 5 years; and 39.2% at 10 years. Callaly et al. (2016) followed 567 participants of the North Dublin Population Stroke Study. The reported cumulative incidence of stroke recurrence was 5.4% at 90 days, 8.5% at one year and 10.8% at 2 years with a 2-year case fatality of 38.6%. These findings highlight the value of assessing patients who present with suspected stroke or TIA according to time since onset of symptoms. 

The project is a prospective registry designed to follow patients presenting with TIA or minor stroke over a 5-year period. Patients were included if the event had occurred within the previous 7 days. The preliminary results, which included 4,583 patients recruited from 61 sites in 21 countries from 1997-2003, have recently become available (Amarenco et al. 2016). In terms of stroke etiology, 5.0% of the patients received a new diagnosis of atrial fibrillation, of which 66.8% received anticoagulant therapy before discharge. Carotid stenosis of ≥50% was found in 15.5% of patients, of which 26.9% underwent carotid revascularization before discharge. The one-year estimate of risk of the primary outcome, a composite of death from cardiovascular causes, nonfatal stroke and nonfatal acute coronary syndrome, was 6.2% (95% CI 5.5-7.0%). Estimates of the stroke rate at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively.

Several tools are available to assess the likelihood of recurrent stroke in patients presenting with TIA. After assessing 8 assessment tools, Purroy et al. (2012) reported that ABCD3 and ABCD3V were the best predictors of stroke at 7 and 90 days. The corresponding areas under the curve (AUC) were 0.66 (p=0.004) and 0.69 (p<0.001) at day 7 and 0.61 (p=0.015) and 0.63 (p=0.003), at day 90.  All other tools, including the California Risk Score, ABCD, ABCD2, ABCDI, ABCD2I, SPI-II and ESRS were unable to predict stroke risk beyond chance alone (p>0.05) at either day 7 or 90. Perry et al. (2014) identified 13 independent predictors of stroke recurrence within 7 days and used them to develop the Canadian TIA Score. The AUC for this tool was 0.77 (95% CI 0.73-0.82). The strongest predictors of stroke were established antiplatelet therapy, initial diastolic blood pressure ≥110 mm Hg, and initial blood glucose ≥15 mmol/L. Coutts et al. (2012) reported that for patients with TIA or minor stroke, a CT/CTA performed within 24 hours was predictive of recurrent stroke at 90 days. In fact, a positive CT/CTA was the only clinical or imaging parameter that remained a significant predictor identified in multivariable analysis. 
It remains unclear whether there are differences in progression to stroke associated with different models of care. Neither Paul et al. (2013), nor Martinez-Martinez et al. (2013) reported significant differences in recurrent stroke following TIA in patients who were managed in outpatient clinics or hospital settings, although both authors noted that the costs were significantly increased (up to 5-fold) when patients were managed in hospital. Giles & Rothwell (2007) reported that the risk of recurrent stroke varied considerably depending on the clinical setting, with the lowest risk associated with specialized stroke services, where stroke recurrence was only 0.6% at day 2 and 0.9% at day 7. Patients who have immediate access to services that offer diagnostic testing such as imaging achieve better outcomes. Rothwell et al. (2007) found that immediate access to a stroke unit and timely initiation of prophylactic medication resulted in both fewer recurrent strokes and adverse events for patients compared to patients who had a lengthier delay in receiving this care. 

Detecting atrial fibrillation (AF) after a stroke or TIA is important since it is a major risk factor for subsequent stroke and, once identified, can be effectively treated.  However, AF is under-diagnosed because it is frequently paroxysmal and asymptomatic, and patients do not routinely undergo prolonged screening. The low levels of monitoring were highlighted in a study authored by Edwards et al. (2016). The records of 17,398 consecutive patients presenting with first-ever stroke or TIA with motor or speech deficits, without a known history of AF in sinus rhythm, were reviewed and the utilization of ambulatory ECG monitoring within the first 90 days of the event was assessed. A total of 5,318 patients (30.6%) received at least 24-hour Holter monitoring within 30 days of the index event. The numbers associated with more prolonged Holter monitoring were lower; 2,253 patients (12.9%) and 25 patients (0.1%) underwent 48-hr and >60-hr monitoring, respectively within 90 days. Monitoring with event loop recording was conducted in 139 patients (0.8%) within 90 days. A meta-analysis conducted by Sposato et al. (2015) examined the use of outpatient cardiac monitoring following minor stroke or TIA in 4 distinct phases. The results from the studies that initiated investigations during the second ambulatory period (phase 4), using mobile cardiac outpatient telemetry (n=5), external loop recording (n=7) or implantable loop recording devices (n=7), reported an estimated 16.9% (95% CI 13.0% -21.2%) of patients were diagnosed with AF.
The results from four RCTs and numerous observational studies have demonstrated that prolonged post-stroke ECG monitoring using wearable or insertable devices is effective for improving the detection of paroxysmal AF (number needed to screen range from 8-14), with longer monitoring durations associated with an increased probability of AF detection. In the Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Ischemic Event (EMBRACE) trail (Gladstone et al. 2014), a 30-day ambulatory cardiac event monitor was found to be superior to repeat 24-hour Holter monitoring in identifying AF in 572 patients aged 52 to 96 years (mean=72.5 years) without known AF, who had sustained a cryptogenic ischemic stroke or TIA within the previous 6 months. Atrial fibrillation lasting ≥30 seconds was detected in 16.1% of patients, using the cardiac event monitor compared with 3.2% of patients in the Holter group (absolute difference, 12.9%; 95% CI 8.0 to 17.6; p<0.001; number needed to screen= 8). The cardiac event monitor was also more likely to identify cases of AF lasting longer than ≥2.5 minutes (9.9% vs. 2.5%, absolute difference, 7.4%, 95% CI, 3.4 to 11.3; p<0.001). By 90 days, oral anticoagulant therapy had been prescribed for more patients in the intervention group (18.6% vs. 11.1%, p=0.01). Three-quarters of AF cases identified in the intervention group were detected within the first 2 weeks of monitoring. In a UK trial (Higgins et al. 2013) in which 100 patients with no history of AF and in sinus rhythm were randomized, a strategy of 7-day ECG monitoring in the acute phase post-stroke was found to be superior to standard care for the detection of paroxysmal AF (18% vs. 2%; p<0.05). Significantly more patients who received additional monitoring were started on anticoagulants. The Finding Atrial Fibrillation in Stroke - Evaluation of Enhanced and Prolonged Holter Monitoring (FIND-AF) trial randomized 398 patients over age 60 years (average age 73 years) reported that a strategy of 10-day Holter monitoring started within the first week post stroke and repeated at 3 months and 6 months was superior to standard care, which consisted of an average of 73 hours of inpatient telemetry plus an average of 24 hours of Holter monitoring (Wachter et al. 2016). At 6 months, detection of AF was significantly higher in the prolonged monitoring group (13.5% vs. 4.5%; absolute difference 9%, 95% CI 3.5-14.6, p=0.002; NNS=11). Similar findings were reported in the Cryptogenic Stroke and Underlying AF (CRYSTAL-AF) trial (Sanna et al. 2014) when patients (mean age of 61.5 years) received long-term monitoring with an insertable cardiac monitor (ICM).  At 6 months, the rate of detection of AF was significantly higher among patients assigned to the ICM group (8.9% vs. 1.4%, HR=6.4, 95% CI 1.9- 21.7, p<0.001), compared with those who received standard monitoring using ECG monitoring on a schedule at the discretion of their treating physician. Similar results were reported at 12 months (12.4% vs. 2.0%, HR=7.3, 95% CI 2.6- 20.8, p<0.001). 
The clinical and cost-effectiveness of prolonged ECG monitoring are likely greater for patients with estimated good life expectancy and quality of life, and for those with excessive atrial ectopy, enlarged or poorly contracting left atrium, or elevated natriuretic peptide levels. While prolonged post-stroke ECG monitoring improves AF detection and may lead to a change in patient management from antiplatelet to anticoagulant therapy, there are notable limitations to the available evidence, as clinical trials have not been powered to determine the effect of prolonged ECG monitoring on the rate of recurrent stroke. Device-detected AF is often brief and subclinical and the minimum duration or burden of device-detected AF that warrants initiation of anticoagulant therapy remains uncertain; therefore, expert opinion varies widely. 

Laboratory investigations and assessment of physiological variables as part of a patient’s initial evaluation provides important information for patient management. A small case control study found that maintenance of normal physiological variables within the first three days of stroke has a beneficial effect on outcomes post stroke (Langhorne et al. 2000). Blood biomarkers have been shown to correlate with cerebral lesion size and stroke severity (Kisialiou et al. 2012). Ferrari et al. (2010) found that hypertension, diabetes, possible etiology, acute infection and cardiac abnormalities were all independent predictors of deterioration following TIA or minor stroke, and recommended immediate diagnostic testing for their identification. Together, these findings suggest a complete evaluation of patients presenting with suspected stroke or TIA is beneficial for predicting risk of recurrent stroke and guiding patient management.

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