STROKE AND TIA



















NAVIGATE ESUS Study - Rivaroxaban vs Aspirin for Secondary Prevention of Cryptogenic Stroke, NEJM (2018) [PubMed abstract]
  • The NAVIGATE ESUS study enrolled 7213 patients diagnosed with a cryptogenic stroke
Main inclusion criteria
  • Ischemic stroke on imaging within 7 days - 6 months
  • Age > 49 years (if 50 - 59 years required to have 1 additional vascular risk factor)
  • At least 20 hours of cardiac rhythm monitoring to rule out A fib lasting ≥ 6 minutes
Main exclusion criteria
  • Lacunar infarct
  • ≥ 50% stenosis in arteries supplying the area of ischemia
  • Mechanical heart valve
  • A fib
  • Severe mitral stenosis
Baseline characteristics
  • Average age - 67 years
  • PFO - 7%
  • Aspirin use before qualifying stroke - 17%
  • Previous stroke or TIA - 17%
Randomized treatment groups
  • Group 1 (3609 patients): Rivaroxaban 15 mg once daily
  • Group 2 (3604 patients): Aspirin 100 mg once daily
Primary outcome:
  • Efficacy: first recurrent stroke (including ischemic, hemorrhagic, or undefined stroke) or systemic embolism in a time-to-event analysis
  • Safety: major bleeding at any site in the body
Results

Duration: Trial terminated after a median of 11 months due to lack of benefit
Outcome Rivaroxaban Aspirin Comparisons
Recurrent stroke or systemic embolism 5.1% 4.8% HR 1.07, 95%CI[0.87 - 1.33]
Major bleeding 1.8% 0.7%, HR 2.72, 95%CI[1.68 - 4.39], p<0.001

Findings: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding.
Dabigatran vs Aspirin for Secondary Prevention of Cryptogenic Stroke, NEJM (2019) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=5390 | length = 19 months) in patients who had been diagnosed with cryptogenic stroke
  • Treatment: Dabigatran 150 mg twice daily vs Aspirin 100 mg once daily
  • Primary outcome: Efficacy - recurrent stroke | Safety - major bleeding
  • Results:
    • Recurrent stroke: Dabigatran - 6.6%, Aspirin - 7.7% (p=0.10)
    • Major bleeding: Dabigatran - 1.7%, Aspirin - 1.4% (HR 1.19 95%CI [0.85 – 1.66])
  • Findings: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group.






  • Data from a second study
  • Reference [15]
Risk of stroke after TIA
Time since TIA Cumulative risk of stroke
First 6 hours 1.2%
First 12 hours 2.1%
First 24 hours 5.1%
First 2 days 3.1%
First 7 days 5.2%












CATIS trial - Immediate Blood Pressure Control vs None in Acute Ischemic Stroke, JAMA (2013) [PubMed abstract]
  • The CATIS trial enrolled 4071 Chinese patients with acute ischemic stroke
Main inclusion criteria
  • Ischemic stroke confirmed by CT or MRI
  • Symptom onset within 48 hours
  • SBP of 140 - 220 mmHg
Main exclusion criteria
  • SBP > 220 mmHg
  • DBP > 120 mmHg
  • Treated with fibrinolysis
  • Severe heart failure
  • Atrial fibrillation
Baseline characteristics
  • Average age 62
  • Average BP - 166/97 mmHg
  • Diagnosis of hypertension - 79%
  • Currently treated with BP meds - 49%
  • Stroke subtype: Thrombotic - 78% | Embolic - 5% | Lacunar - 19%
Randomized treatment groups
  • Group 1 (2038 patients) - Antihypertensive medications with goal to lower SBP by 10 - 25% in first 24 hours, and achieve SBP < 140 mmHg and DBP < 90 mmHg within 7 days
  • Group 2 (2033 patients) - No antihypertensive medications during hospitalization
  • Antihypertensive medications included IV enalapril (first line), calcium channel blockers (second line), and diuretics (third line)
  • Upon hospital discharge, antihypertensive medications were prescribed in both groups according to clinical guidelines
  • Median hospital stay was 13 days in both groups
Primary outcome: Composite of death within 14 days or major disability (defined as modified Rankin score 3 - 5) at 14 days or at hospital discharge if earlier than 14 days
Results

Duration: 3 months
Outcome BP control None Comparisons
Primary outcome (at 14 days) 33.6% 33.6% HR 1.0, 95%CI [0.88 - 1.14], p=0.98
Primary outcome (at 3 months) 25.2% 25.3% HR 0.99, 95%CI [0.86 - 1.15], p=0.93
Median modified Rankin score (at 14 days) 2.0 2.0 p=0.70
Overall mortality (at 14 days) 1.2% 1.2% HR 1.0, 95%CI [0.57 - 1.74], p=0.99
Average blood pressure at 24 hours 145/86 153/90 p<0.001
Average blood pressure at Day 7 137/82 147/86 p<0.001

Findings: Among patients with acute ischemic stroke, blood pressure reduction with antihypertensive medications, compared with the absence of hypertensive medication, did not reduce the likelihood of death and major disability at 14 days or hospital discharge.
ENOS trial - Nitric Oxide vs None in Acute Stroke, Lancet (2015) [PubMed abstract]
  • The ENOS trial enrolled 4011 patients with acute stroke
Main inclusion criteria
  • Ischemic or hemorrhagic stroke confirmed by CT or MRI
  • Motor deficit in arm, leg, or both
  • SBP 140 - 220 mmHg
  • Able to be treated within 48 hours of stroke onset
Main exclusion criteria
  • Definite need for BP meds (e.g. thrombolysis)
  • Pure sensory stroke
  • Isolated dysphagia
  • Prior modified Rankin score of 3 - 5
Baseline characteristics
  • Average age 70 years
  • Average BP 167/90
  • Ischemic stroke - 83% | Intracerebral hemorrhage - 16%
  • Diagnosis of hypertension - 65%
  • Taking antihypertensives - 54%
  • Thrombolytic treatment - 10%
Randomized treatment groups
  • Group 1 (2000 patients) - Glyceryl trinitrate 5 mg patch daily for 7 days
  • Group 2 (2011 patients) - No patch
  • The study had another factor in which the subgroup of patients who were taking antihypertensive medications at enrollment (n=2097) were randomized to continue their medications (n=1053) or stop them for 7 days (n=1044)
Primary outcome: Functional outcome assessed with the modified Rankin scale at 90 days after enrollment. /1cores on the modified Rankin scale range from 0 to 6, with a score of zero indicating no symptoms, five indicating severe dependency, and six denoting death.
Results

Duration: 90 days
Outcome Glyceryl trinitrate None Comparisons
Primary outcome (odds ratio of worse outcome with glyceryl trinitrate) 1.01 95% CI [0.91 - 1.13], p=0.83
Overall mortality 12% 13% OR 0.89, 95% CI [0.72 - 1.10], p=0.27
Average blood pressure on Day 1 157/84 164/88 p<0.0001
  • After Day 3, blood pressure did not differ significantly between the two groups
  • In the subgroup of patients (N=2097) who were randomized to continue or stop their BP meds, there was no significant difference at 90 days for the primary outcome (OR 1.05, 95% CI [0.90 - 1.22], p=0.55)
Findings: In patients with acute stroke and high blood pressure, transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke.
ENCHANTED trial - Intensive BP Reduction vs Standard therapy in Acute Stroke treated with Fibrinolysis, Lancet (2019) [PubMed abstract]
  • The ENCHANTED trial enrolled 2227 patients with acute stroke who were eligible for fibrinolysis
Main inclusion criteria
  • Acute ischemic stroke
  • SBP ≥ 150 mmHg
  • Eligible for fibrinolysis with alteplase
  • Randomized within 6 hours of symptom onset
Main exclusion criteria
  • Unlikely to benefit from fibrinolysis
  • Pre-stroke modified Rankin score of 2 - 5
Baseline characteristics
  • Average age 67 years
  • Average BP - 165/90
  • Previous stroke - 19%
  • History of hypertension - 71%
  • Taking antiplatelet drug - 17.5%
Randomized treatment groups
  • Group 1 (1081 patients): Intensive BP lowering with SBP target of 130 - 140 mmHg
  • Group 2 (1115 patients): Standard therapy with SBP target of < 180 mmHg
  • Patients were required to comply with guidelines for the use of thrombolysis which included having a SBP ≤ 185 mm Hg before administration of intravenous alteplase
  • Endovascular thrombectomy was permitted
  • BP treatment was according to local protocols and included IV, oral, and topical BP meds
  • Brain imaging was done at baseline, 24 hours, and as clinically indicated
Primary outcome: Shift in measures of functioning according to the full range of scores on the modified Rankin scale at 90 days (0 = no disability, 6 = death)
Results

Duration: 90 days
Outcome Intensive Standard Comparisons
Average SBP over first 24 hours (mmHg) 144 150 p<0.0001
Primary outcome (intensive vs standard odds ratio) 1.01 p=0.87
Overall mortality 9.4% 7.9% p=0.20
Modified Rankin score of 3 - 6 33.6% 33.6% p=0.99
Intracranial hemorrhage 14.8% 18.7% p=0.014
  • Only 2% of patients received thrombectomy

Findings: Although intensive blood pressure lowering is safe, the observed reduction in intracranial hemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group.









NINDS trial - Alteplase vs Placebo in Acute (< 3 hours) Ischemic Stroke, NEJM (1995) [PubMed abstract]
  • The NINDS trial (part 2) enrolled 333 patients with ischemic stroke
Main inclusion criteria
  • Ischemic stroke with symptoms onset within 3 hours
  • See fibrinolysis criteria for full list of inclusion criteria
Main exclusion criteria
  • Hemorrhagic stroke
  • Onset of symptoms > 3 hours
  • See fibrinolysis criteria for full list of exclusion criteria
Baseline characteristics
  • Average age 67 years
  • Median NIHSS score - 14.5
  • Average BP - 153/85
  • Stroke subtype: Small-vessel occlusive - 12% | Large-vessel occlusive - 42% | Cardioembolic - 45%
  • History of prior stroke - 10%
Randomized treatment groups
  • Group 1 (168 patients) - Alteplase 0.9 mg per kg body weight (max 90 mg) IV
  • Group 2 (165 patients) - Placebo
  • 10% of the alteplase dose was given as a bolus, and the remainder was infused over 60 minutes
  • No anticoagulants or antiplatelet agents were given for 24 hours after treatment
Primary outcome: Global stroke disability score (included Barthel index, Rankin scale, Glasgow, and NIHSS) at 3 months
Results

Duration: 3 months
Outcome Alteplase Placebo Comparisons
Primary outcome (odds ratio of better outcome with alteplase on global scale) 1.7 95%CI [1.2 - 2.6]
Modified Rankin score ≤ 1 39% 26% HR 1.5, 95% CI [1.1 - 2.0], p=0.019
Overall mortality (combined studies) 17% 21% p=0.30
Symptomatic intracranial hemorrhage within 36 hours of treatment (combined studies) 6.4% 0.6% p<0.001
  • There was another part to the study where a separate group of patients (n=291) were randomized to the same treatments and the primary outcome was improvement of ≥ 4 points in the NIHSS score (scale 0 - 42, lower score indicates better function) or resolution of symptoms at 24 hours. In that part, 47% of alteplase-treated patients met the primary outcome compared to 39% of placebo-treated patients (RR 1.2, 95% CI [0.9 - 1.6], p=0.21). [7]

Findings: Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.
ECASS trial - Alteplase vs Placebo in Acute (3 - 4.5 hours) Ischemic Stroke, NEJM (2008) [PubMed abstract]
  • The ECASS trial enrolled 821 patients with ischemic stroke
Main inclusion criteria
  • Ischemic stroke
  • Able to receive study treatment within 3 - 4.5 hours of symptom onset
  • See fibrinolysis criteria for full list of inclusion criteria
Main exclusion criteria
Baseline characteristics
  • Average age 65 years
  • Mean NIHSS score - 11
  • Average BP - 153/84
  • Taking antiplatelet drugs - 32%
  • History of stroke - 11%
Randomized treatment groups
  • Group 1 (418 patients) - Alteplase 0.9 mg per kg body weight (max 90 mg)
  • Group 2 (403 patients) - Placebo
  • The median time to treatment initiation was 3 hrs 58 mins
Primary outcome: Disability at 90 days as assessed by the modified Rankin scale. The scale was dichotomized as a favorable outcome (score 0 or 1) or an unfavorable outcome (score 2 - 6).
Results

Duration: 90 days
Outcome Alteplase Placebo Comparisons
Primary outcome (favorable outcome on modified Rankin) 52.4% 45.2% OR 1.34, 95% CI [1.02 - 1.76], p=0.04
Overall mortality 7.7% 8.4% OR 0.90, 95%CI [0.54 - 1.49], p=0.68
Symptomatic intracranial hemorrhage 7.9% 3.5% OR 2.38, 95%CI [1.25 - 4.52], p=0.006
Any intracranial hemorrhage 27% 17.6% OR 1.73, 95%CI [1.24 - 2.42], p=0.001

Findings: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage.
WAKE-UP trial - Alteplase vs Placebo in Stroke with Unknown Onset and Favorable MRI findings, NEJM (2018) [PubMed abstract]
  • The WAKE-UP trial enrolled 503 patients with ischemic stroke with unknown length of symptom onset and favorable MRI findings
Main inclusion criteria
  • Acute ischemic stroke
  • Stroke symptoms on awakening or could not report the timing of the onset of symptoms
  • Last time patient known to be well > 4.5 hours
  • MRI findings favorable for reperfusion
  • Able to carry out usual activities in their daily life without support before the stroke
Main exclusion criteria
  • Intracranial hemorrhage
  • Lesions larger than one-third of the territory of the middle cerebral artery
  • Planned thrombectomy
  • NIHSS > 25
  • Contraindications to alteplase (see fibrinolysis criteria) except for unknown time of symptom onset
Baseline characteristics
  • Average age 65 years
  • Reason for unknown symptom length: Nighttime sleep - 89% | Daytime sleep - 4.6% | Aphasia, confusion, other - 6.2%
  • Median NIHSS score - 6
  • Median time from symptom recognition to treatment initiation - 3.1 hours
  • Median time that the patient was last known to be well and treatment initiation - 10.3 hours
Randomized treatment groups
  • Group 1 (254 patients): Alteplase 0.9 mg/kg (with 10% administered as a bolus and the remainder by infusion during a 60-minute period)
  • Group 2 (249 patients): Placebo
  • The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients
Primary outcome: Favorable clinical outcome, which was defined as a score of 0 or 1 on the modified Rankin scale 90 days after randomization
Results

Duration: 90 days
Outcome Alteplase Placebo Comparisons
Primary outcome 53.3% 41.8% p=0.02
Overall mortality 4.1% 1.2% p=0.07
Median score on modified Rankin scale at 90 days 1 2 p=0.003
Symptomatic intracranial hemorrhage 2% 0.4% p=0.15

Findings: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days
EXTEND trial - Alteplase vs Placebo in Stroke with Onset Between 4.5 and 9 hours and Favorable CT/MRI findings, NEJM (2019) [PubMed abstract]
  • The EXTEND trial enrolled 255 patients with acute stroke and symptom onset between 4.5 - 9 hours who had favorable CT/MRI findings
Main inclusion criteria
  • Pre-stroke modified Rankin score < 2
  • NIHSS score 4 - 26
  • 4.5 - 9 hours since symptom onset or on awakening with stroke (if within 9 hours from the midpoint of sleep)
  • MRI findings favorable for reperfusion
Main exclusion criteria
  • Intracranial hemorrhage
  • Rapidly improving symptoms
  • Infarct core greater than one-third of the territory of the middle cerebral artery
  • Contraindications to alteplase (see fibrinolysis criteria)
Baseline characteristics
  • Average age 72 years
  • Median NIHSS score - 11
  • Median time from symptoms to therapy - 7.2 hours
  • Awoke with stroke symptoms - 65%
Randomized treatment groups
  • Group 1 (113 patients): Alteplase 0.9 mg/kg (with 10% administered as a bolus and the remainder by infusion during a 60-minute period)
  • Group 2 (112 patients): Placebo
  • After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from the WAKE-UP trial
Primary outcome: Score of 0 or 1 on the modified Rankin scale at 90 days
Results

Duration: 90 days
Outcome Alteplase Placebo Comparisons
Primary outcome 35.4% 29.5% p=0.04 adjusted †| p=0.35 unadjusted
Overall mortality 11.5% 8.9% p=0.53
Symptomatic intracranial hemorrhage 6.2% 0.9% p=0.07
  • † adjusted for baseline age and NIHSS score

Findings: Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group.



  • Reference [5]
Inclusion/exclusion criteria for IV alteplase in patients with acute ischemic stroke
Overview
  • The AHA/ASA 2018 Guidelines for Management of Acute Ischemic Stroke contains a 4 page table that discusses all the eligibility requirements for Alteplase therapy. The table is available here - AHA/ASA 2018 Alteplase eligibility requirements (page e65)
  • The criteria listed below are the main criteria that were used in the NINDS and ECASS III trials. The AHA guidelines have evolved over the years and the criteria published in 2018 differ from the criteria listed below is some instances.
Criteria for patients with ischemic stroke who are to be treated with rt-PA within 3 hours of symptom onset:
  • Inclusion criteria
    • Ischemic stroke causing measurable neurological deficit
    • Onset of symptoms less than 3 hours before beginning treatment
    • Age ≥ 18 years
  • Exclusion criteria
    • Significant head trauma or prior stroke in previous 3 months
    • Symptoms suggestive of subarachnoid hemorrhage
    • Arterial puncture at noncompressible site in previous 7 days
    • History of previous intracranial hemorrhage
    • Intracranial neoplasm, arteriovenous malformation, or aneurysm
    • Recent intracranial or intraspinal surgery
    • Elevated blood pressure (systolic > 185 mmHg or diastolic > 110 mmHg)
      • In some patients, attempts may be made to lower blood pressure below this cutoff
    • Active internal bleeding
    • Acute bleeding diathesis, including but not limited to
      • Platelet count < 100,000/mm³
      • Heparin received within 48 hours, resulting in abnormally elevated aPTT greater than the upper limit of normal
      • Current use of anticoagulant with INR > 1.7 or PT > 15 seconds
      • Current use of direct thrombin inhibitors or Factor Xa inhibitors with elevated sensitive laboratory tests (such as aPTT, INR, platelet count, and ECT; TT; or appropriate factor Xa activity assays)
    • Blood glucose concentration < 50 mg/dl (2.7 mmol/L)
    • CT demonstrates multilobar infarction (hypodensity > 1/3 cerebral hemisphere)
  • Relative exclusion criteria
    • Recent experience suggests that under some circumstances—with careful consideration and weighing of risk to benefit—patients may receive fibrinolytic therapy despite 1 or more relative contraindications. Consider risk to benefit of IV rtPA administration carefully if any of these relative contraindications are present:
      • Only minor or rapidly improving stroke symptoms (clearing spontaneously)
      • Pregnancy
      • Seizure at onset with postictal residual neurological impairments
      • Major surgery or serious trauma within previous 14 days
      • Recent gastrointestinal or urinary tract hemorrhage (within previous 21 days)
      • Recent acute myocardial infarction (within previous 3 months) [5]
Additional criteria for patients with ischemic stroke who are to be treated with rt-PA within 3 to 4.5 hours of symptom onset
  • Inclusion criteria
    • Diagnosis of ischemic stroke causing measurable neurological deficit
    • Onset of symptoms within 3 to 4.5 hours before beginning treatment
  • Relative exclusion criteria
    • Age > 80 years
    • Severe stroke (NIHSS > 25)
    • Taking an oral anticoagulant regardless of INR
    • History of both diabetes and prior ischemic stroke [5]





MR CLEAN trial - Intraarterial Treatment vs Usual Care for Acute Ischemic Stroke, NEJM (2015) [PubMed abstract]
  • The MR CLEAN trial enrolled 500 patients with acute ischemic stroke involving the anterior circulation
Main inclusion criteria
  • Acute ischemic stroke involving the anterior cerebral circulation (distal intracranial carotid, middle cerebral, and anterior cerebral arteries) established by CT angiography, MR angiography or digital-subtraction angiography
  • Intraarterial treatment possible within 6 hours of stroke onset
  • NIHSS score ≥ 2
Main exclusion criteria
  • Intracranial hemorrhage
  • BP > 185/110
  • History of intracerebral hemorrhage
  • Laboratory evidence of coagulopathy
Baseline characteristics
  • Median age 66 years
  • Median NIHSS score - 17
  • History of ischemic stroke - 11%
  • Average SBP - 146
  • Areas involved: Internal carotid - 27% | Middle cerebral - 99% | Anterior cerebral - 0.6%
Randomized treatment groups
  • Group 1 (233 patients) - Usual care + intraarterial treatment (defined as arterial catheterization with a microcatheter to the level of occlusion and delivery of a thrombolytic agent, mechanical thrombectomy, or both)
  • Group 2 (267 patients) - Usual care only
  • In both groups, about 88% of patients received IV alteplase at a median time of 86 minutes
  • In Group 1, 82% of patients were treated with retrievable stents
  • In Group 1, the median time from stroke onset to groin puncture was 4.3 hours
Primary outcome: Median score on the modified Rankin score at 90 days (scale ranges from 0 - 6 with 0 being no symptoms and 6 being death)
Results

Duration: 90 days
Outcome Thrombectomy Usual care Comparisons
Primary outcome (at 90 days) 3 4 odds ratio of better score in Group 1 - 1.66, 95%CI [1.21 - 2.28]
Modified Rankin score of 0, 1, or 2 at 90 days 32.6% 19.1% OR 2.05, 95%CI [1.36 - 3.09]
Overall mortality (at 30 days) 18.9% 18.4% p>0.05
Symptomatic intracerebral hemorrhage 7.7% 6.4% p>0.05
New ischemic stroke in a different vascular territory 5.6% 0.4% p<0.001

Findings: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe.
MR CLEAN trial Two-Year Outcomes, NEJM (2017) [PubMed abstract]

Duration: 2 years
Outcome Thrombectomy Usual care Comparisons
Primary outcome 3 4 odds ratio of better score in Group 1 - 1.68, 95%CI [1.15 - 2.45], p=0.007
Modified Rankin score of 0, 1, or 2 at 90 days 37.1% 23.9% OR 2.21, 95%CI [1.30 - 3.73], p=0.003
Overall mortality 26% 31% HR 0.9, 95%CI [0.6 - 1.2], p=0.46

Findings: In this extended follow-up trial, the beneficial effect of endovascular treatment on functional outcome at 2 years in patients with acute ischemic stroke was similar to that reported at 90 days in the original trial.







AVERT trial - Early Mobilization vs Usual Care after Acute Stroke, Lancet (2015) [PubMed abstract]
  • The AVERT trial enrolled 2014 patients with acute stroke
Main inclusion criteria
  • Acute stroke (ischemic or hemorrhagic)
  • Admitted to stroke center within 24 hours of stroke onset
Main exclusion criteria
  • Pre-stroke modified Rankin score > 2
  • Early deterioration
  • Immediate surgery
  • Subarachnoid hemorrhage
  • Serious medical illness
  • SBP > 220
Baseline characteristics
  • Median age 72.5 years
  • Pre-stroke modified Rankin scores: 0 - 76% | 1 - 14% | 2 - 10%
  • Hemorrhagic stroke: Group 1 - 14% | Group 2 - 11%
  • Received fibrinolysis - 24%
  • Previous stroke - 18%
Randomized treatment groups
  • Group 1 (1054 patients) - Early mobilization (defined as having the following 3 elements: 1. begin within 24 hours of stroke onset 2. focus on sitting, standing, and walking (out-of-bed) activity 3. result in at least three additional out-of-bed sessions to usual care
  • Group 2 (1050 patients) - Usual care at the discretion of individual sites
  • Patients assigned to early mobilization were assisted by PT and nursing staff trained in study procedures
  • The intervention lasted for 14 days or until discharge from stroke unit, whichever was sooner
Primary outcome: Favorable outcome (defined as a modified Rankin score of 0 - 2) at 3 months after stroke. Modified Rankin scale ranges from 0 - 6 with 0 being no disability and 6 being death.
Results

Duration: 3 months
Outcome Early mobilization Usual care Comparisons
Primary outcome 46% 50% OR 0.73, 95%CI [0.59 - 0.90], p=0.004
Median time to first mobilization 18.5 hours 22.4 hours p<0.0001
Median daily sessions of out-of-bed activity 6.5 3 p<0.0001
Median minutes per day of out-of-bed activity 31 10 p<0.0001
Median minutes of total activity over length of stay or until 14 days after stroke 201 70 p<0.0001
Median length of hospital/rehabilitation stay 16 days 18 days N/A

Findings: First mobilization took place within 24 h for most patients in this trial. The higher dose, very early mobilization protocol was associated with a reduction in the odds of a favourable outcome at 3 months. Early mobilization after stroke is recommended in many clinical practice guidelines worldwide, and our findings should affect clinical practice by refining present guidelines; however, clinical recommendations should be informed by future analyses of dose-response associations.













CAPRIE Trial - Clopidogrel vs Aspirin for the Secondary Prevention of CVD, Lancet (1996) [PubMed abstract]
  • The CAPRIE trial enrolled 19,185 patients with a history of stroke, heart attack, or peripheral artery disease
Main inclusion criteria
  • One of the following: recent ischemic stroke (onset ≥ 1 week and ≤ 6 months), recent heart attack (onset ≤ 35 days), history of intermittent claudication (with ABI ≤ 0.85 or history of leg surgery for vascular disease)
Main exclusion criteria
  • Uncontrolled hypertension
  • History of bleeding or bleeding disorder
  • Carotid endarterectomy after qualifying stroke
Baseline characteristics
  • Average age ∼ 62 years
  • Patients with diabetes - 20%
  • Qualifying criteria: Stroke - 33.5% | Heart attack - 33% | Intermittent claudication - 33.5%
Randomized treatment groups
  • Group 1 (9599 patients) - Clopidogrel 75 mg once daily
  • Group 2 (9586 patients) - Aspirin 325 mg once daily
Primary outcome: Composite of stroke, heart attack, or vascular death
Results

Duration: Average of 1.91 years
Outcome Clopidogrel Aspirin Comparisons
Primary outcome (annual rate) 5.3% 5.8% p=0.043
Overall mortality (annual rate) 3.1% 3.1% p=0.71
Primary outcome among patients with stroke as qualifying event (annual rate) 7.2% 7.7% p=0.26
Primary outcome among patients with myocardial infarction as qualifying event (annual rate) 5.0% 4.8% p=0.66
GI bleeding 1.9% 2.6% p<0.05
Any bleeding disorder 9.2% 9.2% p>0.05

Findings: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.
PROFESS study - Aspirin + Dipyridamole vs Clopidogrel for the Secondary Prevention of Stroke, NEJM (2008) [PubMed abstract]
  • The PROFESS study enrolled 20,332 patients with a recent stroke
Main inclusion criteria
  • Age ≥ 50 years
  • Stroke within 90 days or stroke within 90 - 120 days with at least 2 vascular risk factors
Main exclusion criteria
  • Contraindication to antiplatelet therapy
Baseline characteristics
  • Average age 66 years
  • Median time from qualifying event to randomization - 15 days
  • Prior stroke or TIA (before qualifying event) - 24%
Randomized treatment groups
  • Group 1 (10,181 patients) - Aspirin 25 mg + extended-release dipyridamole 200 mg twice a day (ASA-ERPD)
  • Group 2 (10,151 patients) - Clopidogrel 75 mg once daily
Primary outcome: Recurrent stroke of any type
Results

Duration: Average of 2.5 years
Outcome ASA-ERPD Clopidogrel Comparisons
Primary outcome 9% 8.8% HR 1.01, 95%CI [0.92 - 1.11]
Myocardial infarction 1.7% 1.9% HR 0.90, 95%CI [0.73 - 1.10]
Overall mortality 7.3% 7.4% HR 0.97, 95%CI [0.87 - 1.07]
Major bleeding event 4.1% 3.6% HR 1.15, 95%CI [1.0 - 1.32]
Intracranial hemorrhage 1.4% 1.0% HR 1.42, 95%CI [1.11 - 1.83]
Premature treatment discontinuation 29.1% 22.6% p<0.001

Findings: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke.
MATCH Trial - Clopidogrel + Aspirin vs Clopidogrel for the Secondary Prevention of CVD, Lancet (2004) [PubMed abstract]
  • The MATCH trial enrolled 7599 patients with recent TIA or stroke who were at high risk for a recurrent event
Main inclusion criteria
  • Stroke or TIA in previous 3 months + 1 or more of the following (within 3 years): previous ischemic stroke, previous myocardial infarction, angina, diabetes, symptomatic peripheral artery disease
Main exclusion criteria
  • Age younger than 40 years
  • Increased risk of bleeding
  • Severe comorbid condition
Baseline characteristics
  • Average age 66 years
  • Qualifying event: TIA - 21% | Stroke - 79%
  • Prior history of TIA or stroke (before qualifying event) - 46%
  • Previous MI - 5%
  • Symptomatic PAD - 10%
Randomized treatment groups
  • Group 1 (3797 patients) - Aspirin 75 mg once daily + Clopidogrel 75 mg once daily
  • Group 2 (3802 patients) - Placebo + Clopidogrel 75 mg once daily
Primary outcome: Composite of ischemic stroke, myocardial infarction, vascular death (including haemorrhagic death of any origin), or rehospitalization for an acute ischemic event (including unstable angina pectoris, worsening of peripheral arterial disease requiring therapeutic intervention or urgent revascularization, or transient ischaemic attack)
Results

Duration: 18 months
Outcome Aspirin + Clopidogrel Clopidogrel Comparisons
Primary outcome 16% 17% diff 1%, 95%CI [-0.6% to 2.7%], p=0.24
Ischemic stroke 8% 9% diff 0.62%, 95%CI [-0.6% to 1.9%], p=0.35
Myocardial infarction 2% 2% diff -0.13%, 95%CI [-0.7% to 0.5%], p=0.66
Overall mortality 5% 5% diff -0.01%, 95%CI [-1.0% to 1.0%], p=0.99
Life-threatening bleeding 3% 1% diff 1.26%, 95%CI [0.64% to 1.88%], p=<0.0001
Major bleeding 2% 1% diff 1.36%, 95%CI [0.86% to 1.86%], p=<0.0001

Findings: Adding aspirin to clopidogrel in high-risk patients with recent ischaemic stroke or transient ischaemic attack is associated with a non-significant difference in reducing major vascular events. However, the risk of life-threatening or major bleeding is increased by the addition of aspirin.
SOCRATES trial - Ticagrelor vs Aspirin for the Secondary Prevention of CVD, NEJM (2016) [PubMed abstract]
  • The SOCRATES study enrolled 13,199 patients with a recent stroke or high-risk TIA
Main inclusion criteria
  • Acute ischemic stroke (NIHSS score ≤ 5) or high-risk TIA (ABCD² stroke risk score ≥ 4)
  • Patient able to be randomized within 24 hours of event
Main exclusion criteria
  • A fib or other cardioembolic risk factors
  • Fibrinolytic therapy within 24 hours before randomization
  • Taking CYP3A4 strong inhibitor
  • Bleeding disorder
  • History of intracerebral hemorrhage
Baseline characteristics
  • Average age 66 years
  • Qualifying event: TIA - 27% | Ischemic stroke - 73%
  • Taking aspirin before randomization - 32%
  • Taking clopidogrel before randomization - 3.4%
Randomized treatment groups
  • Group 1 (6589 patients) - Ticagrelor 180 mg loading dose followed by 90 mg twice a day
  • Group 2 (6610 patients) - Aspirin 300 mg loading dose followed by 100 mg once daily
  • Placebo doses of opposing therapy were also given to all patients
Primary outcome: Composite of stroke (ischemic or hemorrhagic), myocardial infarction, or death within 90 days
Results

Duration: 90 days
Outcome Ticagrelor Aspirin Comparisons
Primary outcome 6.7% 7.5% HR 0.89, 95%CI [0.78 - 1.01], p=0.07
All stroke 5.9% 6.8% HR 0.86, 95%CI [0.75 - 0.99], p=0.03
Myocardial infarction 0.4% 0.3% HR 1.20, 95%CI [0.67 - 2.14], p=0.55
Overall mortality 1.0% 0.9% HR 1.18, 95%CI [0.83 - 1.67], p=0.36
Major bleeding 0.5% 0.6% HR 0.83, 95%CI [0.52 - 1.34], p=0.45
Premature treatment discontinuation 17.5% 14.7% N/A
Dyspnea 6.2% 1.4% N/A

Findings: In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days
WARSS trial - Warfarin vs Aspirin for the Secondary Prevention of Stroke, NEJM (2001) [PubMed abstract]
  • The WARSS trial enrolled 2206 patients with noncardioembolic ischemic stroke within the past 30 days
Main inclusion criteria
  • Ischemic stroke within 30 days
Main exclusion criteria
  • Stroke secondary to cardioembolic source
  • Stroke due to procedure or carotid stenosis for which surgery was planned
  • INR > 1.4
Baseline characteristics
  • Average age 63 years
  • Prior stroke, TIA, or amaurosis fugax - 28%
  • Qualifying stroke type: Cryptogenic - 26% | Small-vessel or lacunar - 56% | Large-artery, severe stenosis, or occlusion - 11.5%
  • Degree of disability: Severe - 7.5% | Moderate - 29% | Minimal to none - 63%
Randomized treatment groups
  • Group 1 (1103 patients) - Warfarin with target INR of 1.4 - 2.8
  • Group 2 (1103 patients) - Aspirin 325 mg once daily
Primary outcome: Composite of death from any cause or recurrent ischemic stroke at 2 years
Results

Duration: 2 years
Outcome Warfarin Aspirin Comparisons
Primary outcome 17.8% 16%, HR 1.13, 95%CI [0.92 - 1.38], p=0.25
Overall mortality 4.3% 4.8% HR 0.88, 95%CI [0.58 - 1.32], p=0.61
Major hemorrhage 2.2% 1.5% HR 1.48, 95%CI [0.93 - 2.44], p=0.10
  • The INR in Group 1 was in the therapeutic range 71% of the time with an average of 2.1

Findings: Over two years, we found no difference between aspirin and warfarin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage. Consequently, we regard both warfarin and aspirin as reasonable therapeutic alternatives.






CHANCE trial - Clopidogrel + Aspirin vs Aspirin Alone after Minor Stroke or TIA, NEJM (2013) [PubMed abstract]
  • The CHANCE study enrolled 5170 patients with a TIA or minor ischemic stroke within the past 24 hours
Main inclusion criteria
  • Ischemic stroke (NIHSS score ≤ 3) or high-risk TIA (ABCD² score ≥ 4) within last 24 hours
Main exclusion criteria
  • Cardiac source of stroke or TIA (A fib or heart valve disease)
  • History of intracranial hemorrhage
  • Procedure-related TIA or stroke
Baseline characteristics
  • Median age 62 years
  • Qualifying event: Minor stroke - 72% | TIA - 28%
  • Prior history of ischemic stroke (before qualifying event) - 20%
  • Taking aspirin prior to presentation - 11%
Randomized treatment groups
  • Group 1 (2584 patients) - Aspirin 75 - 300 mg on Day 1 followed by 75 mg once daily for 20 days + clopidogrel 300 mg loading dose followed by 75 mg once daily for 90 days
  • Group 2 (2586 patients) - Aspirin 75 - 300 mg on Day 1 followed by 75 mg once daily for 90 days + placebo
Primary outcome: Recurrent stroke (ischemic or hemorrhagic) within 90 days
Results

Duration: 90 days
Outcome Aspirin + Clopidogrel Aspirin Comparisons
Primary outcome 8.2% 11.7% HR 0.68, 95%CI [0.57 - 0.81], p<0.001
Stroke, MI, or cardiovascular death 8.4% 11.9% HR 0.69, 95%CI [0.58 - 0.82], p<0.001
Overall mortality 0.4% 0.4% HR 0.97, 95%CI [0.40 - 2.33], p=0.94
Severe bleeding 0.2% 0.2% HR 0.94, 95%CI [0.24 - 3.79], p=0.94
Any bleeding 2.3% 1.6% HR 1.41, 95%CI [0.95 - 2.10], p=0.09

Findings: Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage.
POINT trial - Clopidogrel + Aspirin vs Aspirin Alone after Minor Stroke or TIA, NEJM (2018) [PubMed abstract]
  • The POINT trial enrolled 4881 patients who presented with minor ischemic stroke or high-risk TIA
Main inclusion criteria
  • Able to be enrolled within 12 hours of AIS or high-risk TIA
  • AIS (NIHSS score ≤ 3) or high-risk TIA (ABCD² score ≥ 4)
Main exclusion criteria
  • TIA symptoms limited to isolated numbness, isolated visual changes, or isolated dizziness or vertigo
  • Fibrinolysis within 1 week
  • Candidates for fibrinolysis, endovascular therapy, or endarterectomy
Baseline characteristics
  • Median age 65 years
  • Taking aspirin before qualifying event - 58%
  • Qualifying event: TIA - 43% | Stroke - 57%
  • Median ABCD² score for TIA patients - 5
  • Median NIHSS score for AIS patients - 2
Randomized treatment groups
  • Group 1 (2432 patients): Clopidogrel 600 mg loading dose then 75 mg once daily + Aspirin 50 - 325 mg once daily for 90 days
  • Group 2 (2449 patients): Placebo + Aspirin 50 - 325 mg once daily for 90 days
Primary outcomes:
  • Efficacy: Risk of a composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes (major ischemic events) on the basis of standard definitions
  • Safety: Risk of major hemorrhage, which was defined as symptomatic intracranial hemorrhage, intraocular bleeding causing vision loss, transfusion of 2 or more units of red cells or an equivalent amount of whole blood, hospitalization or prolongation of an existing hospitalization, or death due to hemorrhage
Results

Duration: 90 days
Outcome Clopidogrel + Aspirin Aspirin Comparisons
Primary outcome (efficacy) 5% 6.5% HR 0.75, 95%CI [0.59 - 0.95], p=0.02
Primary outcome (safety) 0.9% 0.4% HR 2.32, 95%CI [1.10 - 4.87], p=0.02
Primary outcome (combined efficacy and safety) 5.8% 6.8% HR 0.84, 95%CI [0.67 - 1.05], p=0.13

Findings: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone
TARDIS trial - Clopidogrel + Aspirin + Dipyridamole vs Clopidogrel or Aspirin + Dipyridamole after Stroke or TIA, Lancet (2018) [PubMed abstract]
  • The TARDIS trial enrolled 3096 patients who presented to the hospital with ischemic stroke or TIA
Main inclusion criteria
  • AIS with limb weakness, dysphasia, or neuroimaging-positive hemianopia or TIA with at least 10 min of limb weakness or isolated dysphasia
  • Able to be randomized within 48 hours of symptom onset
  • If received fibrinolysis, could be randomized after 24 hours if neuroimaging showed no bleed
Main exclusion criteria
  • Age < 50 years
  • Isolated sensory symptoms, facial weakness, or vertigo or dizziness
  • Presumed cardioembolic stroke or TIA
Baseline characteristics
  • Average age 69 years
  • Taking aspirin before qualifying event - 26%
  • Qualifying event: Stroke - 72% | TIA - 28%
  • Received fibrinolysis - 11%
Randomized treatment groups
  • Group 1 (1556 patients): Clopidogrel 300 mg loading dose then 75 mg once daily + Aspirin 300 mg loading dose then 50 - 150 mg once daily + dipyridamole 200 mg twice daily for 30 days (ASA-ERPD)
  • Group 2 (1540 patients): Either combined aspirin and dipyridamole, or clopidogrel alone using the same loading and maintenance doses
  • After 30 days, participants were treated according to local guidelines, typically with clopidogrel alone or combined aspirin and dipyridamole
Primary outcomes:
  • Efficacy: Incidence and severity of recurrent stroke and TIA during follow-up to 90 days
  • Safety: Bleeding
Results

Duration: 90 days
Outcome Clopidogrel + ASA-ERPD ASA-ERPD or Clopidogrel Comparisons
Primary outcome (efficacy) 6% 7% HR 0.90, 95%CI [0.67 - 1.20], p=0.47
Primary outcome (safety) 20% 9% HR 2.54, 95%CI [2.05 - 3.16], p<0.0001

Findings: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice.


















Women's Health Study - Aspirin vs Placebo for the Primary Prevention of CVD, NEJM (2005) [PubMed abstract]
  • The Women's Health Study enrolled 39,876 female health professionals
Main inclusion criteria
  • Age ≥ 45 years
  • No history of CAD, cerebrovascular disease, cancer, or major chronic illness
Main exclusion criteria
  • Taking aspirin or other NSAID more than once a week
  • Taking anticoagulants or corticosteroids
Baseline characteristics
  • Average age 55 years
  • Current smoker - 13%
  • Hypertension - 26%
  • Dyslipidemia - 30%
  • Diabetes - 2.6%
Randomized treatment groups
  • Group 1 (19,934 patients) - Aspirin 100 mg every other day
  • Group 2 (19,942 patients) - Placebo every other day
Primary outcome: Composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes
Results

Duration: Average of 10.1 years
Outcome Aspirin Placebo Comparisons
Primary outcome 2.4% 2.6% HR 0.91, 95%CI [0.80 - 1.03], p=0.13
Stroke 1.1% 1.3% HR 0.83, 95%CI [0.69 - 0.99], p=0.04
TIA 0.93% 1.2% HR 0.78, 95%CI [0.64 - 0.94], p=0.01
Myocardial infarction 1.0% 0.97% HR 1.02, 95%CI [0.84 - 1.25], p=0.83
Overall mortality 3.1% 3.2% HR 0.95, 95%CI [0.85 - 1.06], p=0.32
GI bleeding 4.6% 3.8% HR 1.22, 95%CI [1.10 - 1.34], p<0.001
GI bleeding requiring transfusion 0.6% 0.5% HR 1.40, 95%CI [1.07 - 1.83], p=0.02
Peptic ulcer 2.7% 2.1% HR 1.32, 95%CI [1.16 - 1.50], p<0.001

Findings: In this large, primary-prevention trial among women, aspirin lowered the risk of stroke without affecting the risk of myocardial infarction or death from cardiovascular causes, leading to a nonsignificant finding with respect to the primary end point







  • Reference [14]
Risk of recurrent stroke after first-ever stroke (N=2874)
Time since first-stroke Cumulative risk of stroke
1 year 7.1%
5 years 16.2%
10 years 24.5%







REDUCE Study- PFO Closure + Antiplatelet Therapy vs Antiplatelet Therapy Alone after Cryptogenic Stroke, NEJM (2017) [PubMed abstract]
  • The REDUCE study enrolled 664 patients with cryptogenic stroke and PFO
Main inclusion criteria
  • Age 18 - 59 years
  • Cryptogenic AIS within 180 days
  • PFO with right-to-left shunt
Main exclusion criteria
  • Occlusion or stenosis ≥ 50% of a major vessel (intracranial arteries, cervical arteries, and aortic arch)
  • Lacunar infarct or small, deep infarction (< 1.5 cm in diameter)
  • Uncontrolled hypertension or diabetes
  • Autoimmune disease
Baseline characteristics
  • Average age - 45 years
  • Previous stroke or TIA before qualifying event - 12%
  • PFO shunt size: Large - 40% | Moderate - 41% | Small - 19%
Randomized treatment groups
  • Group 1 (441 patients): Antiplatelet therapy + PFO closure with Helex Septal Occluder (implanted through late 2012) or the Cardioform Septal Occluder device (implanted from late 2012 on)
  • Group 2 (223 patients): Antiplatelet therapy
  • Antiplatelet therapy consisted of aspirin alone (75 to 325 mg once daily), a combination of aspirin (50 to 100 mg daily) and dipyridamole (225 to 400 mg daily), or clopidogrel (75 mg once daily)
Primary outcomes
  • 1. Clinical ischemic stroke through at least 24 months
  • 2. Total infarcts at 2 years which included clinical ischemic strokes and subclinical infarcts detected on screening MRI at 24 months
Results

Duration: Median 3.2 years
Outcome PFO closure None Comparisons
Clinical ischemic stroke (median 3.2 years) 1.4% 5.4% HR, 0.23; 95%CI [0.09 - 0.62], p=0.002
Total infarcts at 2 years 5.7% 11.3% RR 0.51, 95%CI [0.29 to 0.91], p=0.04
Atrial fibrillation or flutter 6.6% 0.4% p<0.001
Overall mortality 0.5% 0% p=0.55
Device-related serious adverse event (excluding arrhythmia) 1.4% N/A N/A
Procedure-related serious adverse event 2.5% N/A N/A

Findings: Among patients with a PFO who had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation.