Stroke:

Transient ischemic attack (TIA): abrupt onset focal neurological deficit that lasts <24 hours and usually <30 minutes

May or may not result in infarction

Treat as stroke until tissue damage is ruled out on imaging

Highest risk of stroke after a TIA is in the first few days

- 2 days: 3.5%, 30 days: 8%, 90 days: 9.2%

ABCD2 score used to predict the short term risk of stroke after TIA

Stroke: cerebrovascular accident

Classified into two major types:

1. Hemorrhagic – brain hemorrhage due to intracerebral hemorrhage or subarachnoid hemorrhage

- Results in direct irritant effects of blood that is in direct contact with brain tissue

- Causes include cerebral artery aneurysm, arteriovenous malformation, hypertensive hemorrhage and trauma

2. Ischemic – brain ischemia due to atherosclerosis of cerebral vessels, thrombosis, embolism (to cerebral arteries) or systemic

hypoperfusion

Pathophysiology: Normal cerebral blood flow: ~50mL/100g per minute – maintained by cerebral autoregulation

Ischemia: ↓ blood flow: <20mL/100g per minute – cerebral autoregulation is impaired

When blood flow <12 mL/100g per minute – cerebral autoregulation effect is diminished ↓ ATP ↑ Ca damage + cell death

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ISCHEMIC STROKE

Definitions:

Infarct: Necrotic region of tissue

Lacunes: small lesions

Penumbra: surrounding infarct – activated neurons that could survive for days

- if perfuse right away, can salvage

Hemorrhagic Transformation: ischemic tissue transformed to hemorrhage

- an intracerebral hemorrhage from thrombolysis often occurs as a result of hemorrhagic transformation of ischemic tissue

- 2 types: asymptomatic + symptomatic asymptomatic believed to be clinically innocuous (but controversial)

TOAST Classification:

Large artery atherosclerosis

Cardioembolism AFib, valve disease, ischemic heart disease, infective endocarditis

Small-vessel occlusion (Aka lacune)

Stroke of other determined etiology Prothrombotic state, dissections, drug abuse

Stroke of undetermined etiology

Risk Factors:

NON-MODIFIABLE MODIFIABLE, well-documented Potentially modifiable, less well documented

ISCHEMIC STROKE

Age (↑2x/10 years over 55) Gender (♂↑risk,

♀↑complications) Race (↑death in Asians, African

Americans, Hispanics) Family history of stroke Personal history of stroke Low birth weight Sickle cell disease

Hypertension Atrial fibrillation Other cardiac diseases TIA CAD Diabetes Dyslipidemia Alcohol, diet, smoking Sickle cell disease Asymptomatic carotid stenosis Physical inactivity, obesity Drugs: Post-menopausal HRT

Oral contraceptives Migraine Drug and alcohol abuse Hemostatic and inflammatory factors Sleep disordered breathing

INTRAPARENCHYMAL HEMORRHAGE

Vascular malformation Amyloid angiopathy Neoplasm Trauma Acute ischemic stroke

Hypertension Antithrombotic use Thrombolytic Use Coagulopathy Illicit Drug Use

Presentation:

CNS Headache Vertigo Altered LOC Falling Sudden numbness of leg, arm or face

HEENT Loss of vision Double vision Visual field defects Aphasia – trouble speaking Dysarthria

MSK One-sided weakness Hemiparesis Sudden issue with coordination

Neurological deficits and signs of symptoms correlate to location of infarct

Complications:

Early Complications (within 7 days)

Cerebral edema and herniation (within 96 hours)

Expansion of the infarct/recurrent infarction

Hemorrhagic transformation weakened vessels ↑ risk of hemorrhage

Seizures risk present in acute and chronic phase of stroke

Aspiration pneumonitis

Pneumonia dysphagia/swallowing difficulties ↑ risk of aspiration pneumonia

UTI risk ↑ especially if required to insert a foley catheter

VTE

Late complications (> 7 days later)

Clinical depression

Recurrent stroke

Seizure

Aspiration pneumonitis

VTE

Decubitus ulcer

Persistent cognitive or language dysfunction and/or persistent loss of mobility

Spasticity

Scores:

ABCD2 score: helps justify if should be managed as in-patient or out-patient stroke clinic

National Institutes of Health Stroke Scale: Performed upon admission to determine type of care and to assess progress of stroke

Modified Rankin Score (*Often used as outcomes in stroke RCTs): Global score

Differential Diagnosis: Clinical situations mimicking stroke

Psychogenic Lack of objective cranial nerve findings, neurological findings in a non-fascicular distribution, inconsistent examination

Seizures Hx of seizures, witnessed seizure activity, post-ictal period

Hypoglycemia Hx of diabetes, low serum glucose, ↓ LOC

Migraine with aura Hx of similar events, preceding aura, headache

Wernicke's encephalopathy Hx of ETOH abuse, ataxia, ophthalmoplegia, confusion

CNS abscess Hx of drug abuse, endocarditis, medical device implant with fever

CNS tumour Gradual progression of sx, other malignancy, seizure at onset

Drug Toxicity Lithium, phenytoin, carbamazepine

Laboratory Tests:

Diagnostic Tests:

*Head CT – Computerized Tomography – Identifies ischemia and arterial occlusions – Most commonly used imaging test (immediate availability) – Difficulty visualizing deep, small infarcts

*CTA – Computerized Tomography Angiogram – Focuses on the blood vessels

*Almost all patients will get head CT or CTA, unless poor renal function

If above negative but still high suspicion of stroke, use MRI stroke protocol (long waitlist)

MRI – Magnetic Resonance Imaging

– More sensitive than CT in detecting ischemic changes and acute vs chronic origin

– Greater spatial resolution

– Expensive; limited availability

– CI: pacemakers, metal implants (e.g. in eye), claustrophobia, patient confusion, etc.

Other tests:

♦ MRA – Magnetic Resonance Angiogram: Detects intracranial stenosis, vessel occlusion

♦ Transcranial Doppler – Identification of intracranial stenosis

– Has been used to monitor thrombolysis effects and to determine prognosis

♦ ECG – baseline CV assessment, detection of arrhythmia, concurrent MI

♦ TTE/TEE – examine if any clots in the heart

GoTs:

1. Reduce the ongoing neurological injury

2. Restore quality of life and function

3. Prevent complications, 2o to immobility and neurological dysfunction

4. Decrease mortality

5. Prevent stroke recurrence

Ischemic Stroke Continuum

Primary Prevention Hyper-Acute Acute Stroke Treatment Secondary Prevention

Timing Prior to stroke < 6 hours Days 1 – 14 (> 24 hours) > Day 14 – 30

Goal ↓ risk of first stroke Prevent early mortality and morbidity

↓ risk of recurrent stroke

Management Control risk factors Oxygen, BP, glucose, temperature, volume status, reperfusion

Antiplatelet or TPA + Supportive Care + VTE Prophylaxis

Antiplatelet + Control Risk Factors

Treatment for Ischemic Stroke:

1. OXYGEN – Hypoxemia = low concentration of oxygen in blood

Common causes: Partial airway obstruction, Hypoventilation, Aspiration, Atelectasis, Pneumonia

Supplemental O2 – for patients with SaO2 < 95% - Goal: >92% (evidence is not conclusive)

o If normal oxygen saturation, not required routinely

2. POSITIONING

Supine: use if patient is NOT hypoxic – may offer advantages in term of cerebral perfusion

Elevate head of bed to 15-30o: if patient at risk of obstruction, aspiration, ↑ intracranial pressure

3. BLOOD PRESSURE MANAGEMENT

Hyperacute: Hypertension is common in acute stroke patients and ↑ risk of sICH (symptomatic intracranial hemorrhage)

♦ Ischemic stroke patients eligible for thrombolytic therapy

– Treat to a target < 180/105 mmHg

– May reduce the risk of intracranial hemorrhage

♦ Ischemic stroke patients not eligible for thrombolytic therapy

High ID of intracranial stenosis (50-99%)

~90% negative predictive value

– Only treat extreme BP elevation (SBP > 220mHg or DBP > 120mmHg)

– Goal: ↓ BP by ~15% but not more than 25% over 1st

24 hours

High BP:

– PROs: could improve cerebral perfusion of ischemic tissue

– CONs: could exacerbate edema and hemorrhagic transformation of ischemic tissue; encephalopathy, cardiac complications, renal insufficiency

(transformation: when have ischemic tissue and then it bleeds in the area)

No consistent evidence to support BP targets post-ischemic stroke; aggressive BP lowering may ↓ perfusion and worsen ischemia

Options: may need to start NG tubes to give meds regularly as there are complications with fluctuating BP meds

Not receiving tPA *GOAL: ↓ 15% BP* Receiving tPA *higher bleeding risk ∴ target BP < 185/110 for initiation and <180-105 for maintenance

– within 48 h of ischemic stroke/TIA target SBP < max of 220mHg and DBP < 120 *Do not lower unless >220/120*

– Discontinuing or holding BB therapy may lead to rebound tachycardia or rapid afib. Stopping BB to meet BP targets is not recommended, although a lower dose may be considered

– Consider holding a patient's normal antihypertensive regimen on medication reconciliation form. Consider maintaining BB therapy as per above.

– Physician to R/A BP regimen 48 hours after stroke/TIA when patient is neurologically stable

Options: ♦ Captopril 12.5-25mg SL Q30 min PRN SBP>220 and/or DBP>120 – Max dose 150mg/24 hrs

Options: ♦ If systolic BP > 180mmHg *OR* diastolic BP > 105mmHg – IN CRITICAL AND SPECIAL CARE AREAS ONLY:

Labetalol 10mg IV, then 10-20mg IV Q10min PRN (Max dose: 300mg/24h) Contact physician if BP not controlled after 3 doses HOLD labetalol if HR < 60BPM MONITOR BP 5, 10 and 15 minutes after each dose VS and neurovital signs Q15min until 4 hrs after BP controlled *OR*

– Hydralazine 5-10mg IV Q15min PRN Contact physician if BP not controlled after 3 doses Monitor BP 15 and 30 mins after each dose of hydralazine VS and neurovital signs Q15min until 4 hours after BP controlled

– Captopril 12.5mg SL Q30min PRN (Max: 150mg/24h)

4. VOLUME STATUS

Hypovolemia hypoperfusion, exacerbation of ischemia, renal impairment

Hypervolemia ↑ brain edema, stress on myocardium

Hypotonic solutions (ie D5 ½NS) may worsen edema because they distribute intracellularly

NS distributes more evenly into extracellular spaces

Recommendation: Use isotonic solutions for volume replacement (0.9% NS)

5. GLUCOSE MANAGEMENT

Hyperglycemia: common during acute stroke (40%)

- Stress reaction impaired glucose metabolism

- Associated with ↑ infarct volume by MRI

- ↑ risk of sICH in patients treated with rtPA – tPA is contraindicated if BG < 2.7 or > 22 mmol/L

Hypoglycemia: rare (likely related to antidiabetic meds)

*stroke mimics and seizures – look for autonomic and neurological symptoms and check blood glucose*

Target: 7.7 – 10 mmol/L for all hospitalized patients

6. TEMPERATURE

Hyperthemia in acute ischemic stroke – associated with poor neurological outcomes and worsening of stroke

o ~1/3 of admitted stroke patients will be hyperthermic within 1st

hours of acute stroke onset

Determine cause – e.g. secondary to a cause of stroke (infective endocarditis), complication of stroke (pneumonia, UTI, sepsis)

Treat the cause if identified

Antipyretics to ↓ temperature if hyperthermic (>38oC)

- Insufficient evidence to support hypothermia to ↓ metabolic demands (goal is to avoid fever)

7. FIBRINOLYSIS

Alteplase (Recombinant Tissue Plasminogen Activator):

Alteplase binds to fibrin in a thrombus and converts entrapped plasminogen to plasmin which dissolves the clot

(thrombus: strands of fibrin + plasminogen) ∴ helps re-perfuse and save cells in penumbra (original infarction remains)

- Onset: <1 hr

- Duration: Fibrinolytic activity persist up to 1 hr after infusion terminated

- Elimination: primarily hepatic – t1/2: 5 minutes

- Dose: 0.9mg/kg (max 90mg), 10% given as bolus, 90% infused over 1h

Indications:

1. Diagnosis of ischemic stroke causing measurable neurological deficit *AND*

2. Patient has been assessed by a neurologist, CT scan performed and read, can be transported if necessary and alteplase treatment can

be initiated within 4.5 hours of a well established symptom onset

Goal: door to needle time < 60 mins for tPA – time is brain!

- Blood glucose is the only lab test that must precede tPA administration

o Unless hx of anticoagulant use, abnormal bleeding

Contraindications

Absolute Contraindications: History of intracranial hemorrhage, neoplasm, vascular

malformation (except meningioma), or aneurysm Stroke, intracranial surgery or head injury within 3 mos Arterial puncture at non-compressible site within 7 days Symptoms of stroke suggestive of subarachnoid hemorrhage Witness seizure with postictal residual neurological impairments

unless clearly attributable to acute stroke Evidence of active bleeding or acute trauma (fracture) on exam Acute bleeding diathesis Persistent hypertension (BP >185/110) Anticoagulant use within 48 hrs and a prolonged PTT and/or

INR > 1.7 (Anti-Xa levels take too long) Platelet < 100,000 x 10

9/L

Blood glucose < 2.7 mmol/L or > 22 mol/L CT changes showing major extensive early infarct signs Evidence of intracranial hemorrhage on pretx noncontrast head

CT

Relative Contraindications: Recent acute MI (within previous 3 months) Neurological signs clearing spontaneously; signs minor & isolated Pregnancy Age less than 18 years Within 14 days of major surgery or serious trauma Recent GI or urinary tract hemorrhage (within previous 21 days) Post MI pericarditis or aortic dissection

Precautions within 3-4.5 hrs following onset of stroke symptoms: Oral anticoagulant treatment Age > 80 yo Severe hemispheric stroke as assessed clinically (NIHSS score >

25) or a stroke with major early infarct CT signs involving more than 1/3 of the middle cerebral artery territory

Combination of previous stroke and DM Major surgery or trauma within previous 3 months

Monitoring:

Vital signs Q15min x 2 hours, then Q30min x 6 hours, then Q1hr until 24hr post-tx

Neurovital signs Q1hr x 6 hrs, then reassess Signs of clinical deterioration: new headache, acute

hypertension, nausea or vomiting, evidence of bleeding Angioedema CT head – repeat 24 hours after alteplase

Precautions:

No tooth brushing or shaving x 24hr Avoid central venous access and arterial punctures x 24hr Avoid placing indwelling catheter during infusion and for at

least 30 mins after Avoid insertion of an NG tube in the 1

st 24hrs

Toxicity Monitor for Plan

Severe Bleed Cerebral, retroperitoneal, genitourinary, respiratory tract, gastrointestinal

D/C alteplase CBC

Minor Bleed Superficial hematoma, hematuria, hemoptysis, epistaxis, gingival bleeding

D/C alteplase? CBC

Intracranial Hemorrhage New onset H/A, N/V, new onset symptoms D/C alteplase CT scan CBC

Orolingual angioedema reactions

Swelling of tongue, lips or oropharynx (Risk↑in ACE-I, infarctions w/ insular/frontal cortex)

D/C alteplase IV diphenhydramine 50mg, IV methylprednisolone or hydrocortisone 100mg, IV ranitidine 50mg, Manage airway – when resolved and angioedema was mild, may restart tPA Epinephrine: use should be weighed against risk of sudden HTN and ICH

Acute HTN BP >180/105 mm Hg IV antihypertensive

Q15min vitals

If there is clinical deterioration (new headache, acute HTN, nausea and vomiting) or evidence of bleeding:

D/C tPA infusion

CT scan STAT

INR, fibrinogen, CBC

Evidence for tPA:

NINDS: 2 Part RCT, R, PC, DB n= 654, ICH ruled out. tPA 0.9mg/kg within 3h of stroke onset.

– Bottom line: Functional benefit at 90 days, but ↑ risk of ICH. No mortality benefit.

ECASS III: R, PC, DB n = 821. Included patients with sx onset within 3-4.5h. tPA 0.9mg/kg vs.placebo

– Bottom line: If treated between 3-4.5h, functional benefit (mRS<2) at 90 days persists but smaller.

IST-3: Open lab, PC < n = 3035. Acute ischemic stroke, sx onset within 6h, ICH ruled out. No age restriction.

tPA 0.9mg/kg within 6 hr of symptom onset.

– Bottom line: No functional benefit, higher risk of early death within the 1st

6 days

Endovascular therapy 6 positive trials published in 2014-2015

Indicated for: > 18 yo, functionally disabling stroke (NIHSS >2, ASPECTS >6), can be performed +/0 tPA treatment, imaging (small to

moderate ischemic core), intracranial artery occlusion (in the anterior circulation, mod to good collateral circulation, r/o ICH)

o Exclusion: BP > 185/110, IV tPA > 0.9mg/kg, evidence of coagulation abnormalities

Time to tx: within 6hr of symptom onset, up to 12 hrs

– Must be transferred to a stroke centre with expertise in 2nd

generation stent retrievers (only at VGH)

Good functional outcome at 90 days (mRS < 2) but existing conflicting studies/results

8. ANTI-PLATELET THERAPY:

If NOT on antiplatelet + NOT receiving tPA: 160mg-325mg ASA STAT after imaging excludes ICH and dysphagia screening performed

– acute ASA therapy ↓ risk of early recurrent ischemic stroke

If treated with TPA: delay ASA until 24 h post-thrombolysis scan has excluded ICH

In all patients: continue ASA 81 – 325mg daily indefinitely or until alternative anti-thrombotic started

o Clopidogrel may be considered in patients on ASA prior to stroke or TIA as an alternative

o If dysphagic, ASA may be given by enteral tube (80mg daily) or 325mg PR daily

Might consider combination of ASA and clopidogrel for initiation within 24 hours of a minor ischemic stroke or TIA and for continuation

for 90 days

o But…Longer-term use of ASA 81mg and clopidogrel 75mg is not recommended for the use for secondary stroke prevention due

to an increased risk of bleeding and mortality

Evidence:

IST, 1997 (N=19435): ASA 300mg within 48h of stroke onset vs. Placebo (f/u: 14 ds + 6 mos)

– ARR 1.1% for recurrent ischemic stroke (NNT 83 @14ds), NSS for all-cause mortality + hemorrhagic stroke

CAST, 1997 (N=21106): ASA 160mg within 48h of stroke onset vs. Placebo (f/u: 4 wks + discharge)

– ARR 0.5% for recurrent ischemic stroke (NNT 200 @4wks), ARR = 0.6% (NNT 167 @4wks) for all-cause mortality, NSS for hemorrhagic

stroke + death – younger patients with different types of stroke, compared to IS

CHANCE 2013 (N=5170):

ASA 75-300mg LD 75mg daily x 21ds + clopidogrel 300mg LD 75mg daily x 90d vs. ASA 75-300mg LD 75mg daily + placebo

– Recurrent ischemic stroke: ARR 3.5% (NNT = 29 @90ds), NSS for all-cause mortality, hemorrhagic stroke, severe bleeding

– Chinese-only population with high stroke risk (NIHIS <4) which aren't as aggressively treated for HTN, diabetes, hyperlipidemia

– POINT trial extended and still enrolling for North American population

9. VTE PROPHYLAXIS

High risk of DVT and PE – more likely to occur in 1st

3 months after stroke

- PEs account for 10% of deaths after stroke

AHA/ASA 2013 Guidelines: SC administration of anticoagulants is recommended for tx of immobilized pts to prevent DVT

CHEST 2012 Guidelines:

- Initiate within 48 hrs after stroke onset. If admin alteplate, 24hr after admin of thrombolytic therapy (alteplase)

- Low dose SC heparin or LMWH (LMWH = UFH in prevent DVT; Heparin ↓ risk of DVT and PE by 60%)

Canadian Stroke Best Practice Guideline (2015): Based on CLOTS 3 – patients at high risk of VTE should be started on thigh-high

intermittent pneumatic compression (IPC) devices or pharmacological VTE Px immediately if no contraindication (e.g systematic or

intracranial hemorrhage. At present, there is no direct evidence to suggest the superiority of one approach over the other

o Monitor: skin integrity daily, wound care consult if skin breakdown begins (IPC ↑ risk of skin breaks)

IPC devices should be taken off when:

- Patient becomes mobile

- At discharge from hospital

- If any AEs develop

- After 30 days of use (whichever comes first)

Secondary Stroke Prevention:

1. LIFESTYLE MANAGEMENT

Healthy balanced diet: Mediterranean type diet – high in vegetables, fruit, whole grains, fish, nuts, olive oil

Sodium intake <2g/day

Exercise :

Goal: 150 mins of moderate to vigorous activity per week, >10 min per session

PT involvement at initiation if ↑ falls risk, comorbid disease

Weight: BMI 18.5-24.9 kg/m2 or waist circum < 88cm (women), <102cm (men)

Alcohol

- Women: max 10 drinks/week (no more than 3 drinks on a single occasion)

- Men: max 15 drinks/week (no more than 4 drinks on a single occasion)

OC and HRT – discontinue, consider alternatives

Recreational drug use – refer patients for support and resources for dealing with drug addiction

Smoking cessation – refer patients to smoking cessation clinic and BC Quit Now Program

Sleep apnea (risk factor)

– screen for sleep apnea in patients with stroke or TIA

– refer to sleep specialist for management of OSA

– avoidance of hypnotics, sedatives; weight loss; CPAP; dental appliances

2. BLOOD PRESSURE

Long-term management: First stroke: For every 10 mmHg ↑ in DBP, risk of stroke ↑ by 50%

10/5mmHg ↓ in BP is associated with 30-40% ↓ in risk of stroke

Study N Patient Population Intervention & Comparison Primary Outcome Recurrent Stroke

Cardiovascular & Cerebroavascular Stroke

HOPE Stroke

Sub-group analysis of HOPE

1013 with previous stroke

High risk cardiovascular

Ramipril 10mg1 vs. Placebo Composite

(MI, Stroke, CV death)

0

↓ for 1o stroke

0

PROGRESS R, DB, PC

6104 Stroke within previous 5 years +/- HTN

Perindopril 4mg vs. Placebo ↓ 5/3 mmHg

Fatal and non-fatal stroke

0 0

Perindopril 4mg + Indapamide vs. Placebo ↓ 12/5 mmHg

↓ ?effect d/t combo

or more ↓ BP

↓ ?effect d/t combo or

more ↓ BP

PRoFESS R, DB, PC Factorial

20,332 Ischemic stroke within 90 days

Telmisartan 80mg/d vs. Placebo (+ Standard of care – incl. other BP meds)

Recurrent Stroke 0

0

SPS3 R, Open, MC

3,020 Recent (<180d) lacunar stroke

SBP target 130-149 vs. SBP < 130

Recurrent stroke 0 0

Tips and Tricks

Blood pressure reduction

- Prevent recurrent stroke, cardiovascular events

- Benefit seen in hypertensives and normotensives

Absolute target BP not defined

- Benefits seen with 10/5 mmHg reduction

- CHEP < 140/90 mmHg, <130mmHg in diabetic patients

Lifestyle modifications and pharmacologic therapy

- Diuretic + ACEI reasonable option

- May begin >24 hours post-stroke, depending on stability (but not in the immediate acute phase of stroke)

3. ANTIPLATELET THERAPY

Options: ASA (80-325mg) daily; combined ASA (25mg) + ER dipyridamole (200mg) BID; or clopidogrel (75mg) daily

ATTC 2009 Meta-analysis: ASA vs. no antiplatelet therapy

1o Prevention:

– Serious vascular events (MI, stroke or vascular death): NNT 1667

– Ischemic stroke: NSS

– Extracranial bleeds: NNH 3334

2o Prevention:

– Serious vascular events (MI, stroke or vascular death): NNT 67

– Ischemic stroke: NNT 625

– Extracranial bleeds: very incompletely reported

Vascular mortality: NSS

Compared to ASA

Comparator (Comp)

Study Primary Outcome Bleeding Compared to ASA?

ASA Comp ASA Comp

Clopidogrel CAPRIE 1996

5.83% 5.32% 9.28% 9.27% SAME

ARR: 0.51; NNT 195 NSS

ASA + Clopidogrel CHARISMA 2006

7.3% 6.8% 1.3% 2.1% WORSE Similar efficacy but ↑ bleeding risk with DAPT + NSS for mortality

NSS P < 0.001

SPS3 2012

2.7% 2.5% 0.79% 1.7% SIMILAR with all-cause death benefit (2.1% vs.1.4%)

ARR: 0.2, NSS p < 0.001

ASA + Dipyridamole (not often well tolerated d/t headaches)

ESPIRIT 2006

16% 13% 3.85% 1.93% BETTER

ARR: 3; NNT 33 NSS

ESPS-2 1998

19% 14.9% 8.2% 8.7%

ARR: 4.1; NNT 24 NSS

Ticlopidine TASS 19% 17% Ticlopidine: Diarrhea, rash, neutropenia

?SIMILAR

ARR: 2%, NNT 50

Warfarin WARSS 2001

16% 17.8% RR 1.61 (1.38-1.89) ↑ minor hemorrhage, but NSS for major

WORSE Similar efficacy but ↑ bleeding risk with warfarin

ARR: 1.8%; NSS

Compared to Clopidogrel

Comparator (Comp)

Study Primary Outcome Bleeding Compared to ASA?

Clopidogrel Comp ASA Comp

ASA CAPRIE 1996

5.32% 5.83% 9.27% 9.87% SAME (more diarrhea and rashes than ASA)

ARR: 0.51; NNT 195 NSS

ASA + Clopidogrel MATCH 2004 (high risk pts)

12% 12% 1% 2% WORSE

NSS P < 0.0001, NNH = 50

ASA + Dipyridamole PRoFESS 2008

8.8% 9% 3.6% 4.1% ?SIMILAR but not non-inferior and not well tolerated

Not Non-inferior NSS

Tips and Tricks

Similar to ASA

- Clopidogrel

- Efficacy: Warfarin; Clopidogrel + ASA (but ↑ bleeding)

Superior efficacy to ASA

- ASA + Dipyridamoke

- Ticlopidine

- Both are less well tolerated than ASA

SIMILAR to clopidogrel:

- ASA + dipyridamole

Choose based on efficacy, safety, patient factors, cost

ASA reasonable first-line choice

– ANTIPLATELET MANAGEMENT IN PATIENTS WITH INTRACRANIAL ARTERIAL STENOSIS

SAMMPRIS Trial: Stenting vs. Aggressive Medical Therapy for Intracranial Arterial Stenosis

MC RCT. N = 451 patients with recent TIA/CVA due to IC artery stenosis

Percutaneous transluminal angioplasty and stenting (PTAS) + medical therapy vs. Medical therapy only (ASA 325mg daily for entire f/u +

Clopidogrel 75mg daily x 90 days)

o 1o outcome: Stroke or death within 30 ds after enrollment or after revascularization for qualifying lesion beyond 30 days

PTAS + Medical Tx: 20.5% vs. Medical Tx only: 11.5%, P = 0.009

SAMMPRIS was extrapolated to support use of DAPT for up to 3 months in patients with stroke or TIA 2o to ICA (severe stesnosis of 70-

99% of a major intracranial artery)…but no head to head trials of DAPT to ASA or plavix in this context

4. LIPID MANAGEMENT

Modest relationship between LDL and risk of stroke – Lower LDL lower risk of stroke

Target LDL of < 2mmol/L, or a 50% ↓ in LDL from baseline

SPARCL trial – atorvastatin 80mg daily if LDL > 2.6mmol/L (evidence is stronger with ator)

- Recurrent stroke HR 0.84 (NNT = 53 x5y), fatal stroke HR 0.57 (NNT =143), hemorrhagic stroke HR 1.66 (NNH = 107 – no excess fatal

hemorrhagic stroke)

- TNT: 80 vs 10mg (CVA HR 0.77, Stroke HR 0.75)

Heart Protection Study – simvastatin 40mg daily

- High risk cardiovascular patients – 1820 patients with previous stroke (not all patients had previous stroke/TIA)

- Simvastatin reduced vascular events, non-fatal stroke

- 27% RRR for stroke, 1.6% ARR, NNT = 63 x 5.5 yrs

Meta-analysis in high risk cardiovascular population

- Statins reduced the risk of stroke (OR 0.81)

Risk factors for statin-induced myopathy: dose of statin; advanced age (particularly > 80), female sex, possibly Asian descent, fraility,

polypharmacy/drug interactions, renal/hepatic dysfunction, genetic polymorphisms, alcohol

In a patient with a recent stroke…what is the optimal lipid-lowering strategy to reduce the risk of stroke?

SPARCL (Atorvastatin 80mg vs Placebo, N = 4731, Mean LDL = 3.43, Stroke or TIA within previous 1-6 months, no known CAD)

- High dose atorvastatin

↓ risk of fatal stroke, major coronary events

May be associated with more hepatotoxicity

Reasonable option in patients with

o Ischemic stroke

o LDL 2.6 – 4.9 mmol/L

Fibrates not effective at reducing stroke risk

5. DIABETES MANAGEMENT:

Diabetes: Established risk factor for ischemic stroke

Approximately two fold increased risk of stroke

Independent predictor of recurrent stroke

- 9.1% of recurrent stroke attributable to diabetes

In obese patients with T2DM, metformin

- Reduced macrovascular complications

- Reduced stroke

Study N Patient Population Intervention and Comparison Major Results

ACCORD 10,251 62 y/o, A1c 8.1%, T2DM< CV disease Intensive (A1c < 6%) vs. Conventional (A1c 7-7.9%)

Primary outcome: NSS Non-fatal stroke: NSS All-cause mortality: ↑ in intensive group

ADVANCE 11,140 66 y/o, A1c 7.5%, T2DM, CVD Intensive (A1c < 6.5%) vs. Conventional (A1c ~7%)

Macrovascular: NSS Non-fatal stroke: NSS Nephropathy: ↓ in intensive group

PROACTIVE 5,238 61 y/o; A1c 7.8%; T2DM, CVD, Stroke (19%)

Pioglitazone vs. Placebo Primary outcome: NSS Subgroup of previous stroke: ↓ CV events in pioglitazone group

Evidence lacking that diabetes control decreases risk of recurrent stroke. Manage diabetes by CDA guidelines.

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HEMORRHAGIC STROKE:

Pathophysiology: Less well known

Weakened/diseased blood vessel ruptures

Neurotoxicity caused by components found in the blood

and various degradation products

↑ in intracranial pressure due to additional blood which

may lead to herniation and death