STROKE AND TIA























  • 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%











Overview
  • Blood pressure elevations are common during acute ischemic stroke
  • Extreme blood pressure elevations can be detrimental to the heart, brain, and kidneys. Moderate blood pressure elevations may be advantageous because they improve cerebral perfusion to ischemic tissue.
  • The ideal blood pressure range in acute stroke has not been determined. The CATIS and ENOS studies detailed below evaluated different blood pressure regimens in patients with ischemic stroke who did not receive fibrinolysis. The ENCHANTED study compared intensive blood pressure reduction to guideline-based therapy in patients who did receive fibrinolysis.
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.
AHA recommendations for blood pressure control in acute ischemic stroke
Patients eligible for fibrinolysis
  • Blood pressure should be carefully lowered (see fibrinolysis)
  • SBP lowered to < 185 mmHg
  • DBP lowered to < 110 mmHg [32]

Patients who are not considered for fibrinolysis
  • In patients with acute ischemic stroke, early treatment of hypertension is indicated when required by comorbid conditions (eg, concomitant acute coronary event, acute heart failure, aortic dissection, postthrombolysis, sICH, or preeclampsia/eclampsia)
  • Lowering BP initially by 15% is probably safe
  • In patients with BP ≥ 220/120 mmHg who did not receive IV alteplase or thrombectomy and have no comorbid conditions requiring acute antihypertensive treatment, the benefit of initiating or reinitiating treatment of hypertension within the first 48 to 72 hours is uncertain
  • It might be reasonable to lower BP by 15% during the first 24 hours after onset of stroke
  • Starting or restarting antihypertensive therapy during hospitalization in patients with BP > 140/90 mmHg who are neurologically stable is safe and is reasonable to improve long-term BP control unless contraindicated [32]
  • Many patients will have spontaneous declines in blood pressure in the first 24 hours following a stroke [5]
StraightHealthcare analysis
  • The 3 trials above found no benefit of aggressive blood pressure control in patients with ischemic stroke
  • The current AHA guidelines are supported by these trials






Overview
  • Fibrinolysis is the dissolution of blood clots with medications. rt-PA is the most common medication used to dissolve clot. See blood clot dissolution illustration.
  • Tissue plasminogen activator (t-PA) is a naturally occurring protein that acts by enhancing the conversion of plasminogen to plasmin. Plasmin causes dissolution and lysis of blood clots. Recombinant tissue plasminogen activator (rt-PA) is a synthetic version of (t-PA). First generation tissue plasminogen activators (ex. streptokinase , urokinase) are not selective for plasminogen bound to fibrin and may lead to higher bleeding rates. rt-PA is selective for plasminogen that is bound to fibrin, and therefore it is more selective for blood clots. The most common rt-PA used for stroke treatment is alteplase (Activase®). Other rt-PAs are not currently approved for stroke treatment, although a study published in 2018 found another rt-PA called tenecteplase to be superior to alteplase for reperfusion and clot dissolution. [PMID 29694815]
Fibrinolysis trial
  • Four trials that showed a benefit with fibrinolysis are detailed below. The trials vary by the inclusion criteria they used to enroll patients. The NINDS and ECASS trials used length of time since symptom onset to enroll patients. The WAKE-UP and EXTEND trials primarily used MRI perfusion imaging, which can show hypoperfused but salvageable regions of brain, as enrollment criteria.
    • NINDS - symptom onset < 3 hours
    • ECASS - symptom onset 3 - 4.5 hours
    • WAKE-UP - unknown symptom onset with favorable MRI findings
    • EXTEND - symptom onset between 4.5 and 9 hours with favorable CT/MRI findings
  • The inclusion/exclusion critieria from the NINDS and ECASS trials currently serve as the foundation for selecting patients for fibrinolysis
  • Three other trials - ECASS, ECASS II, and ATLANTIS - did not find a benefit with fibrinolysis compared to placebo. These trials differed from the NINDS and ECASS III trials in that patients could be enrolled up to 6 hours after stroke onset and only 14% of patients were treated within 3 hours. [6]
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.
AHA/ASA 2018 fibrinolysis recommendations
  • IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is recommended for selected patients who may be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state. See fibrinolysis criteria for a review patient eligibility.
  • IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is also recommended for selected patients who can be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well. See fibrinolysis criteria for a review patient eligibility.
  • For otherwise eligible patients with mild stroke presenting in the 3- to 4.5-hour window, treatment with IV alteplase may be reasonable. Treatment risks should be weighed against possible benefits.
  • In otherwise eligible patients who have had a previously demonstrated small number (1–10) of cerebral microbleeds on MRI, administration of IV alteplase is reasonable.
  • In otherwise eligible patients who have had a previously demonstrated high burden of cerebral microbleeds (>10) on MRI, treatment with IV alteplase may be associated with an increased risk of symptomatic intracerebral hemorrhage, and the benefits of treatment are uncertain. Treatment may be reasonable if there is the potential for substantial benefit. [34]
  • Cerebral microbleeds are small, chronic hemorrhagic foci (< 5 mm) that have been increasingly detected on MRIs as technology has advanced. The clinical significance of these hemorrhages is unknown.
StraightHealthcare analysis
  • Fibrinolysis improves the chance of a favorable outcome in ischemic stroke by 7 - 13%. After the onset of stroke symptoms, fibrinolysis should be initiated as soon as possible. The NINDS study found a benefit up to 3 hours after symptom onset and the ECASS trial showed a benefit up to 4.5 hours. The WAKE-UP and EXTEND trials showed a benefit beyond 4.5 hours in patients with favorable brain imaging.
  • Fibrinolysis increases the risk of symptomatic intracranial hemorrhage by 4 - 6%. Intracranial hemorrhage can lead to death and severe disability.
Inclusion/exclusion criteria for IV alteplase in patients with acute ischemic stroke
  • 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]



Overview
  • Endovascular treatment of stroke involves running a catheter through the arteries and positioning it close to the blood clot in the brain. The catheter can then be used to deliver devices (stents, mechanical extractors, etc.) and drugs (rt-PA) directly to the clot.
  • Interventions that utilize retrievable stents have been shown to be beneficial in a number of studies (see trials below). Retrievable stents are wire meshes that are placed along the area of occlusion in the artery. The stent expands, and in doing so, becomes embedded in the clot. The stent is then retrieved (retracted) pulling the clot with it.
  • After a number of successful trials, the AHA/ASA published guidelines for the use of retrievable stents in 2018
Mechanical thrombectomy trials
  • Thrombectomy with stent retrievers has been shown to be superior to usual care in the treatment of acute ischemic stroke
  • The first study to show a clear benefit with stent retrievers was the MR CLEAN trial detailed below. After MR CLEAN, a handful of other studies also confirmed a benefit with these devices (see other thrombectomy trials < 6 hours below). Studies were then performed to test the devices in patients with stroke symptoms for > 6 hours (see thrombectomy trials > 6 hours after stroke onset below). These studies also found a benefit, and in 2018, the FDA approved the Trevo clot retrieval device to treat certain stroke patients up to 24 hours after symptom onset.
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.
AHA/ASA recommendations for mechanical thrombectomy
Fibrinolysis and thrombectomy
  • Patients eligible for intravenous rt-PA should receive intravenous rt-PA even if endovascular treatments are being considered
  • In patients under consideration for mechanical thrombectomy, observation after IV alteplase to assess for clinical response should not be performed.

Patients should receive endovascular therapy with a retrievable stent if they meet all the following criteria:
  • Prestroke modified Rankin score of 0 to 1
  • Causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1)
  • Age ≥ 18 years
  • NIHSS score ≥ 6
  • ASPECTS score ≥ 6
  • Treatment can be initiated (groin puncture) within 6 hours of symptom onset

Other considerations
  • Although the benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for carefully selected patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the MCA segment 2 (M2) or MCA segment 3 (M3) portion of the MCAs
  • Although the benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for carefully selected patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries
  • Although its benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have prestroke mRS score >1, ASPECTS <6, or NIHSS score <6, and causative occlusion of the internal carotid artery or proximal MCA (M1). Additional randomized trial data are needed.
  • In selected patients with AIS within 6 to 16 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria, mechanical thrombectomy is recommended
  • In selected patients with AIS within 16 to 24 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy is reasonable.



Overview
  • Most stroke guidelines recommend early mobilization after a stroke; however, these same guidelines do not define what early mobilization is or how it should be instituted
  • The AVERT trial, published in 2015, compared a protocol of early mobilization to usual care in over 2000 patients with acute stroke
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.
AHA/ASA early mobilization recommendations
  • It is recommended that early rehabilitation for hospitalized stroke patients be provided in environments with organized, interprofessional stroke care
  • High-dose, very early mobilization within 24 hours of stroke onset should not be performed because it can reduce the odds of a favorable outcome at 3 months.
StraightHealthcare analysis
  • The AVERT study found that early mobilization actually led to worse outcomes in stroke patients. The results are counterintuitive and go against most current guidelines.
  • The absolute difference between groups was small (4%), but the large study size led to significant results. In a secondary analysis, there was no significant difference in overall Rankin scores between groups.
  • The ideal time to initiate mobilization after stroke is unknown, and likely varies by patient population. Given the available information, providers may want to encourage earlier mobilization in healthier patients with less severe strokes. Sicker patients with more severe strokes should probably be eased into mobilization.










Overview
  • For patients without an indication for anticoagulation (e.g. atrial fibrillation), lifelong antiplatelet therapy is recommended in all patients who have experienced a stroke or TIA
  • Studies comparing different antiplatelet regimens are detailed below. A study that compared warfarin to aspirin is also summarized.
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.
AHA/ASA recommendations
Patients with an indication for anticoagulation
  • Patients with an indication for anticoagulation (ex. atrial fibrillation, venous thromboembolism, mechanical heart valve) should receive anticoagulation alone
  • Patients with an indication for anticoagulation who cannot receive anticoagulation should receive aspirin alone

Patients who do not have an indication for anticoagulation (one of the following):
  • Aspirin 50 - 325 mg once daily (first-line)
  • Aspirin + dipyridamole 25/200 (Aggrenox®) twice a day (second-line)
  • Clopidogrel 75 mg once daily (third-line) [29]
  • In patients presenting with minor stroke, treatment for 21 days with dual antiplatelet therapy (aspirin and clopidogrel) begun within 24 hours can be beneficial for early secondary stroke prevention for a period of up to 90 days from symptom onset (see dual antiplatelet therapy below) [32]
StraightHealthcare analysis
  • Aspirin, clopidogrel, and aspirin + dipyridamole (Aggrenox®) all appear to be equally effective for the secondary prevention of stroke
  • There is no proven benefit of dual antiplatelet therapy, and it may be harmful in some cases
  • In the SOCRATES trial, ticagrelor was not significantly better than aspirin for the primary outcome (p=0.07), but it was superior for preventing all strokes (p=0.03). The study was short, lasting only 90 days.
  • The WARSS trial found that warfarin was no better than aspirin in preventing death or stroke in patients with a history of noncardioembolic ischemic stroke. Warfarin had a trend toward greater risk of major hemorrhage.
  • In another warfarin trial [PMID 15800226], 569 patients with 50 - 99% stenosis of a major intracranial artery were randomly assigned to warfarin (INR 2 - 3) or aspirin (1300 mg a day). Patients were enrolled within 90 days of suffering a noncardioembolic TIA or stroke. The primary endpoint was a composite of ischemic stroke, brain hemorrhage, or death from vascular cause. The trial was stopped after 1.8 years when the warfarin group was found to have a significantly higher incidence of death (9.7% vs 4.3%, p=0.02) [17]
  • Antiplatelet agents are safer than anticoagulants in patients with a history of noncardioembolic ischemic stroke



Overview
  • Long-term dual antiplatelet therapy has not been found to be superior to single agent therapy for the secondary prevention of stroke
  • Three studies have looked at the effects of short-term dual antiplatelet therapy (≤ 90 days) after ischemic stroke or TIA. Those studies are detailed below.
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.
AHA/ASA recommendations
  • The AHA/ASA 2018 stroke treatment guidelines state the following about short-term dual antiplatelet therapy: "In patients presenting with minor stroke, treatment for 21 days with dual antiplatelet therapy (aspirin and clopidogrel) begun within 24 hours can be beneficial for early secondary stroke prevention for a period of up to 90 days from symptom onset." [32]
StraightHealthcare analysis
  • The CHANCE study found that short-term dual antiplatelet therapy for 21 days was beneficial in preventing recurrent stroke in high-risk individuals while the POINT trial did not show a clear benefit with 90 days of dual therapy
  • The CHANCE trial was performed in China where risk factor control (ex. hypertension, diabetes) is often suboptimal compared to developed nations. Also, Asians tend to be poor CYP2C19 metabolizers which means clopidogrel is not as active in this population. These factors along with the shorter duration of dual therapy likely led to the lower bleeding risk seen in the trial.
  • The POINT trial was published after the AHA/ASA guidelines were compiled. It's unclear if its results would have affected their recommendation.
  • In the TARDIS trial, clopidogrel + Aggrenox was found to be harmful when compared to either agent alone















Overview
  • A number of studies have looked at the use of aspirin in the primary prevention of stroke
  • In general, these studies have found no significant effect of aspirin in preventing strokes [3,11,12]
  • The Women's Health Study detailed below was an enormous study that compared aspirin to placebo in the primary prevention of a number of outcomes
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
USPSTF recommendations
AHA recommendations
  • Aspirin is recommended to reduce the risk of heart attack and stroke in patients with a 10-year risk of cardiovascular events from 6 - 10% (see Framingham risk calculator to calculate risk)
  • Aspirin (81 mg daily or 100 mg every other day) can be useful for prevention of a first stroke among women whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment
  • Aspirin is not helpful in patients at low risk for stroke
  • Aspirin is not useful for preventing a first stroke in persons with diabetes or diabetes plus asymptomatic peripheral artery disease (defined as an ankle brachial pressure index ≤ 0.99) in the absence of other established cardiovascular disease [3]
StraightHealthcare analysis
  • For the most part, aspirin has not been found to have an overall beneficial effect in the primary prevention of strokes
  • The Women's Health Study was an enormous study that found a slight decrease in stroke risk with aspirin (absolute risk reduction 0.2%, NNT - 500) at a cost of more GI bleeding (absolute risk increase - 0.8%, NNH - 125)
  • A more recent smaller study that enrolled patients at high risk for vascular disease found no significant effect of aspirin in preventing strokes (see AAA study)
  • If aspirin has an overall benefit in the primary prevention of strokes, the effect is likely very small and limited to people at very high risk




  • 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%






Overview
  • Patent Foramen Ovale (PFO) is a congenital heart defect that is characterized by a hole between the left and right atrium
  • It is one of the most common heart defects with an estimated prevalence of 20 - 26% in the general population
  • In theory, a PFO could allow a blood clot to travel from the venous system to the arterial system by providing a route for the clot to bypass the lungs. Once the blood clot reaches the arterial system, it can cause a stroke.
  • In some studies, PFOs have been found more frequently in patients who have suffered a cryptogenic stroke. This has led researchers to study the effects of closing PFO defects on stroke risk. [2]
  • Three studies published in 2012 - 2013 (CLOSURE (2012), RESPECT (2013), PC Trial (2013)) compared PFO closure to medical therapy. In all 3 studies, PFO closure was not significantly better than medical therapy. The RESPECT trial had the best results with a trend towards lower recurrent stroke risk in the PFO closure group (p=0.08).
  • In 2016, the FDA approved the Amplatzer PFO Occluder for secondary stroke prevention in patients with a patent foramen ovale. The Amplatzer PFO Occluder was studied in the RESPECT Trial and the PC Trial.
  • In 2017, two more PFO closure studies were published. Contrary to the previous studies, these studies did find PFO closure to be superior to medical therapy. One of the trials, the REDUCE trial, is detailed below. The other trial can be found here - CLOSE Trial (2017)
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.
AHA/ASA 2014 recommendations for secondary prevention in patients with PFO
  • It is unknown if anticoagulation is superior to antiplatelet therapy. Antiplatelet therapy is recommended in patients who do not have an indication for anticoagulation.
  • If a venous source of embolism is identified, anticoagulation is indicated. If anticoagulation is contraindicated, then an inferior vena cava filter is reasonable.
  • For patients with a cryptogenic ischemic stroke or TIA without evidence of DVT, PFO closure is not recommended
  • For patients with a cryptogenic ischemic stroke or TIA with evidence of DVT, PFO closure by a transcatheter device might be considered depending on the risk of recurrent DVT [29]
AAN 2016 practice advisory on recurrent stroke with PFO
  • Physicians should not routinely offer percutaneous PFO closure to patients with cryptogenic ischemic stroke
  • In rare cases such as recurrent strokes despite optimal medical therapy, the Amplatzer PFO Occluder may be offered
  • In the absence of an indication for anticoagulation, there is insufficient evidence to determine if anticoagulation is superior to antiplatelet therapy in preventing recurrent strokes [31]
StraightHealthcare analysis
  • Previous studies did not find a clear benefit with PFO closure where the most recent studies did. In their discussion, the authors of the REDUCE trial note that discontinuation of antiplatelet therapy after PFO closure was allowed in the previous trials where antiplatelet therapy was continued in the later trials. This may account for the differing outcomes.
  • It's important to note that PFO closure conferred a 6% risk of new-onset A fib/A flutter. This means patients who underwent PFO closure lowered their stroke risk by about 5% while increasing their A fib risk by 6%. The long-term net effect of this trade-off is unclear.