Introduction to Biostatistics

Acute Medical Acute Medical Stroke TherapyStroke Therapy

Gregory W. Albers, MDGregory W. Albers, MD

Professor of Neurology and Professor of Neurology and Neurological SciencesNeurological Sciences

Director, Stanford Stroke CenterDirector, Stanford Stroke Center

Acute Medical Acute Medical Treatment of StrokeTreatment of Stroke

• Restore Blood FlowRestore Blood Flow– ThrombolyticsThrombolytics– Mechanical devicesMechanical devices

Stroke progression Stroke progression or recurrent or recurrent thromboembolismthromboembolism – AnticoagulantsAnticoagulants– Antiplatelet agentsAntiplatelet agents

How would you treat this patient?

72 yo male with aphasia and right hemiparesis

NIH =18

• If he presents at 2 hours?• If he presents at 5 hours?

NINDS tPA Stroke TrialNINDS tPA Stroke Trial

0

10

20

30

0

10

20

30

tPA tPAPlacebo Placebo

31

20 9

8

20

1

NIHSS Excellent Recovery (%)

Total Death Rate (%)

Hemorrhagep < .05

New England Journal, 1995

Large Randomized Trials of IV tPA Large Randomized Trials of IV tPA for Treatment of Acute Strokefor Treatment of Acute Stroke

Study N Dose Time Window Study N Dose Time Window

ECASS I ECASS I 650 650 1.1 1.1 0 – 6 0 – 6

NINDS NINDS 624624 0.9 0.9 0 – 3 0 – 3

ECASS II ECASS II 800800 0.9 0.9 0 – 6 0 – 6

ATLANTIS A 142ATLANTIS A 142 0.9 0.9 0 – 6 0 – 6

ATLANTIS BATLANTIS B 619619 0.9 0.9 3 – 5 3 – 5

Pooled AnalysisPooled Analysis

Odds Ratios for Favorable OutcomeOdds Ratios for Favorable Outcome

TimeTime Odds Ratio 95% (CI) Interval Odds Ratio 95% (CI) Interval

0-900-90 2.8 2.8 1.8 - 4.51.8 - 4.5

91-18091-180 1.5 1.5 1.1 - 2.11.1 - 2.1

181-270181-270 1.4 1.4 1.1 - 1.91.1 - 1.9

271-360271-360 1.2 1.2 0.9 - 1.50.9 - 1.5

Stroke CodeStroke Code

• Who is eligible for tPA?Who is eligible for tPA?

• What needs to be checked What needs to be checked before starting the tPA infusion?before starting the tPA infusion?

• Common errors to avoidCommon errors to avoid

Early Infarct Signs: Guidelines for Early Infarct Signs: Guidelines for Patients with Clearly Established Stroke Patients with Clearly Established Stroke

Onset and Treatment Within 3 hrsOnset and Treatment Within 3 hrs

• tPA eligibletPA eligible

• not predictive of not predictive of an unfavorable an unfavorable response to tPAresponse to tPA

• insufficient datainsufficient data

• withholding tPA withholding tPA recommended recommended (Level C data )(Level C data )

Subtle early infarct signs (regardless of size)

Extensive andclearly identifiable hypodensity (>1/3 MCA territory)

Stroke CodeStroke Code

• Who is eligible for tPA?Who is eligible for tPA?

• What needs to be checked What needs to be checked before starting the tPA infusion?before starting the tPA infusion?

• Common errors to avoidCommon errors to avoid

Stroke CodeStroke Code

Nursing – if patient is found to have symptoms of a Nursing – if patient is found to have symptoms of a strokestroke• Confirm symptoms with resource RN immediatelyConfirm symptoms with resource RN immediately• Resource RN calls primary teamResource RN calls primary team• Pt’s RN calls Page Operator to initiate Stroke Pt’s RN calls Page Operator to initiate Stroke

CodeCode• Then gather:Then gather:

Brief historyBrief history Reason for thinking patient had a strokeReason for thinking patient had a stroke Last time patient seen normalLast time patient seen normal Current vital signsCurrent vital signs

Stroke CodeStroke Code

Neurology Resident – will be paged by page Neurology Resident – will be paged by page operator on operator on stroke code pagerstroke code pager with text with text message : message : “Stroke Code: Room xxxx”“Stroke Code: Room xxxx”

• Must respond to bedside within Must respond to bedside within 5 minutes5 minutes• If patient is thought to be having a stroke If patient is thought to be having a stroke

then:then:– Activate Brain Attack Team (BAT) Code Activate Brain Attack Team (BAT) Code

ImmediatelyImmediately

Stroke CodeStroke Code

Brain Attack Team consists of:Brain Attack Team consists of:– Critical Care Crisis RNCritical Care Crisis RN– CT TechCT Tech– TransportTransport– Nursing SupervisorNursing Supervisor– Stroke Fellow/Attending Stroke Fellow/Attending (specify)(specify)

Stroke CodeStroke Code

Neurology ResidentNeurology Resident

• Carries Carries “stroke code” “stroke code” pagerpager• Responds to Stroke Code immediatelyResponds to Stroke Code immediately• Determines if Brain Attack Team (BAT) Determines if Brain Attack Team (BAT)

needs to be activatedneeds to be activated• If yes:If yes:

• Orders labsOrders labs• Orders CT or MRIOrders CT or MRI• EKG if neededEKG if needed• NIHSSNIHSS

Stroke CodeStroke Code

Stroke Fellow/AttendingStroke Fellow/Attending• CT or MRI scan evaluationCT or MRI scan evaluation• Determines if tPA criteria is met or if Determines if tPA criteria is met or if

Neurosurgery/Neuroradiology needs to be Neurosurgery/Neuroradiology needs to be consultedconsulted

• Confirms NIHSSConfirms NIHSS• Writes tPA orders if appropriateWrites tPA orders if appropriate• Family communication and consentFamily communication and consent

How Often Should Full Dose Anticoagulation Be Used for Treatment of Acute Stroke?

A. Often used for multiple stroke subtypesA. Often used for multiple stroke subtypes B. Rarely used, except for cardioembolicB. Rarely used, except for cardioembolic C. Rarely used for any stroke subtypeC. Rarely used for any stroke subtype

Guidelines for Guidelines for Anticoagulant TherapyAnticoagulant Therapy

Urgent administration of anticoagulants Urgent administration of anticoagulants

has not yet been associated with has not yet been associated with lessening the risk of early recurrent lessening the risk of early recurrent stroke or improving outcomes. Because stroke or improving outcomes. Because it can increase the risk of brain it can increase the risk of brain hemorrhage, routine use cannot be hemorrhage, routine use cannot be recommendedrecommended..

American Heart Association, 2003

Guidelines for Guidelines for Anticoagulant TherapyAnticoagulant Therapy

Anticoagulants are Anticoagulants are notnot recommended for recommended for

any subgroup of patients with acute stroke any subgroup of patients with acute stroke based on any presumed mechanism or based on any presumed mechanism or location (e.g., cardioembolic, large vessel location (e.g., cardioembolic, large vessel atherosclerotic, vertebrobasilar, or atherosclerotic, vertebrobasilar, or “progressing” stroke) because data are “progressing” stroke) because data are insufficientinsufficient..

American Academy of Neurology / AHA, 2003

Anticoagulation for Anticoagulation for Acute Stroke Acute Stroke

Heparin in Acute Stable Stroke (n=212)Heparin in Acute Stable Stroke (n=212)

Stroke progression Stroke progression ImprovementImprovement

PlaceboPlacebo 20%20% 24% 24%

HeparinHeparin 17%17% 27% 27%

Duke, Ann Int Med 1986

International Stroke TrialInternational Stroke TrialRecurrent Stroke Within 14 DaysRecurrent Stroke Within 14 Days

(N = 19,435)(N = 19,435)

Nadroparin (Fraxiparin) Nadroparin (Fraxiparin) Stroke StudiesStroke Studies

TOAST StudyTOAST Study

TOAST StudyTOAST Study

Treatment of Acute

Cardioembolic Stroke

*no benefit in cardioembolism subgroup

Recent Trial Results

TrialTrial Recurrent Stroke Recurrent Stroke (%)(%)

IST (AF subgroup) Heparin 2.8(N = 3169) No heparin 4.9

TOAST (cardioembolism) Danaparoid 0(N = 266) Placebo 1.6

HAEST (all with AF) Dalteparin 8.5(N = 449) Aspirin 7.5

TAIST* HD Tinzaparin 3.3(N = 1484) LD Tinzaparin 4.7

Aspirin 3.1

Risk of Early Stroke Recurrence

Multiple recent emboli

Mechanical heart valve

Atrial fibrillation + high risk features

Established intra-cardiac thrombus

Treatment of AcuteCardioembolic Stroke

Risk of Hemorrhagic Complications

Anticoagulation increases the risk of extracranial hemorrhage by about 2%

Spontaneous hemorrhagic transformation is common and usually asymptomatic

Anticoagulation increases the risk of symptomatic ICH by about 2%

Treatment of AcuteCardioembolic Stroke

Risk Factors for Symptomatic ICH

Infarct size

Timing of reperfusion (12 - 48 hours)

Excesssive anticoagulation / tPA

Heparin bolus?

Severe hypertension?

Treatment of AcuteCardioembolic Stroke

Aspirin forAspirin forTreatment of Acute Stroke Treatment of Acute Stroke

• International Stroke Trial International Stroke Trial (IST, N = 19,435) (IST, N = 19,435)

• Chinese Acute Stroke Trial Chinese Acute Stroke Trial (CAST N = 21,106)(CAST N = 21,106)

International Stroke TrialInternational Stroke TrialRecurrent Stroke Within 14 DaysRecurrent Stroke Within 14 Days

International Stroke TrialInternational Stroke Trial

Guidelines for Guidelines for Aspirin TherapyAspirin Therapy

• Early aspirin therapy (160-325 mg/day) is Early aspirin therapy (160-325 mg/day) is recommended recommended Grade 1AGrade 1A

• Delay aspirin for at least 24 hours after tPADelay aspirin for at least 24 hours after tPA

• Aspirin can be used safely in combination Aspirin can be used safely in combination with low doses of subcutaneous heparinwith low doses of subcutaneous heparin

Acute Ischemic Stroke

Guidelines for Guidelines for Acute Stroke TherapyAcute Stroke Therapy

• tPA is recommended for eligible patients within tPA is recommended for eligible patients within

3 hours of stroke onset 3 hours of stroke onset Grade 1AGrade 1A

• Aspirin is recommended for non-tPA eligible Aspirin is recommended for non-tPA eligible patients patients Grade 1AGrade 1A

• Use of full-dose anticoagulation with Use of full-dose anticoagulation with intravenous, subcutaneous, or low molecular intravenous, subcutaneous, or low molecular weight heparins or heparinoids should be weight heparins or heparinoids should be avoided avoided Grade 2BGrade 2B

ACCP, 2004