Achieving Favorable Outcomes in Mild Stroke:

Is It the tPA or Just a Stroke of Luck?

Melanie Jaeger, PharmD

PGY1 Pharmacy Resident

Department of Pharmacotherapy and Pharmacy Services, University Health System

Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, UT Health San Antonio

November 16, 2018

Learning Objectives:

1. Summarize assessment, diagnosis, and management of patients with acute ischemic stroke2. Define mild stroke and understand associated morbidity3. Discuss literature regarding the role of tPA in patients with mild stroke, including those with non-disabling deficits4. Identify mild stroke patients in whom tPA treatment is appropriate

Jaeger 2

Assessment Questions:

1. For eligible patients with acute ischemic stroke, alteplase should be administered within what time frame? a. 60 minutes from arrival at the hospital b. 60 minutes from stroke onset c. 4.5 hours from stroke onset d. 6 hours from stroke onset e. Both a & c

2. American Heart Association/American Stroke Association Guidelines recommend against administering tPA for all mild stroke patients with a NIHSS score <5.

a. True

b. False

3. Rates of symptomatic intracranial hemorrhage are lower in mild stroke compared to more severe stroke.

a. True

b. False

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE

Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within

72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***

Faculty (Speaker) Disclosure: Melanie Jaeger has indicated she has no relevant financial relationships to disclose relative to

the content of her presentation.

Jaeger 3

Stroke Background

I. Stroke Defined1

a. Sudden neurological dysfunction resulting from an abrupt decrease in blood perfusion to the brain

b. Two major subtypes

i. Ischemic (85%)

ii. Hemorrhagic (15%)

II. Epidemiology2

a. An estimated 7.2 million Americans >20 years old have had a stroke

b. Annually, approximately 795,000 people experience a stroke event

i. First time stroke: 610,000 people

ii. Recurrent: 185,000 people

c. Lifetime risk for stroke at 65 years old:

i. Men: 14.5%

ii. Women: 16.1%

d. Fifth leading cause of death

i. Someone dies from stroke every 4 minutes

ii. Accounts for 1 of every 20 deaths in the United States

iii. Underlying cause of death in 133,103 people per year

e. Mortality2

Figure 1. Cumulative All-Cause Mortality Post-Stroke

i. Mortality in hemorrhagic stroke > ischemic stroke

ii. Mortality rates from 9% in patients 65-74 years old to 23% in those >85 years

iii. Approximately 30% higher mortality in the “stroke belt,” which has existed since 1940

1. “Belt” includes North and South Carolina, Georgia, Tennessee, Mississippi, Alabama, Louisiana, and

Arkansas

2. “Buckle” (North and South Carolina, Georgia) stroke rates are 40% higher

f. Morbidity2

i. Among top 18 diseases contributing to years lived with disability

ii. In 2003, only 44% of Medicare patients discharged after stroke could return home

Figure 2. Morbidity Post-Stroke (2011)

10.5% 30

days 21.2% 1 year 39.8% 5 years

Home health care

12% Inpatient

rehab 19%

Skilled nursing facility

25%

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Acute Ischemic Stroke (AIS)

I. Etiology and Pathophysiology

Table 1. Stroke Risk Factors2

Modifiable Risk Factors Non-Modifiable Risk Factors

Hypertension Female

Diabetes mellitus Family History

Hyperlipidemia African American > Asian > Caucasian

Smoking Previous vascular events

Obesity

Estrogen Use

Cardiovascular Disease

Atrial Fibrillation

a. Pathophysiology

i. Ischemic injury compromising vascular supply to the brain1,3

1. Core

(a) Area of ischemia with <10-25% blood flow

(b) Function cannot be recovered

2. Penumbra

(a) Outer layers with less ischemia

(b) Blood supplied by collateral vessels

(c) Function may recover with timely intervention

ii. Stroke death and disability largely due to cerebral edema3,4

iii. Ischemic stroke can be categorized by location and occlusion source

ICA: internal carotid artery, MCA: middle cerebral artery, VA: vertebral arteries

Figure 3. Ischemic Stroke Subtypes1,5

II. Signs and Symptoms

a. Neurologic deficits

i. FAST acronym for public awareness1

1. Facial droop

2. Arm drop

3. Speech disturbance

4. Time

Large artery atherosclerosis

Occlusion of major brain artery or branch cortical

artery

ICA, MCA, VAs, and basilar artery

Cardioembolic

Cardiac source

Mechanical valves, atrial fibrillation, endocarditis

Small-artery/lacunar

Exact mechanism not understood

Affected vessels too small for imaging

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Figure 4. Symptoms by Infarct Location1

III. Stroke Severity Assessment

a. National Institutes of Health Stroke Scale (NIHSS) (Appendix A)

i. 42-point serial measure of neurological deficit6,7

1. NIHSS 0-5: minor stroke

2. NIHSS 6-15: moderate stroke

3. NIHSS 16-25: moderate/severe stroke

4. NIHSS >25: very severe, life-threatening stroke

ii. NIHSS score strongly predicts long-term outcomes in acute ischemic stroke (AIS)7

1. Each additional point on NIHSS decreases likelihood of a favorable outcome:

(a) 7 days: 24%

(b) 3 months: 17%

2. Score ≥16 suggests high likelihood of death or severe disability (favorable outcome in 20%)

Stroke Outcomes Assessment

I. Outcome Scales8

a. Modified Rankin Scale (mRS)

i. Assesses functional ability

ii. Most frequently used morbidity scale in ischemic stroke trials

iii. Score 0-1 considered “favorable outcome” in most trials9,10

Left hemisphere

•Aphasia

•Right hemiparesis

•Right hemianopia

Right hemisphere

•Left hemispatial extinction/inattention

•Left hemiparesis

•Left hemianopia

Posterior circulation

•Diplopia

•Bulbar palsies

•Dysphagia

•Unilateral dysmetria

•Incoordination

•Reduced consciousness

Table 2. Modified Rankin Scale8

Score Definition

0 No symptoms

1 No significant disability. Can carry out usual activities.

2 Slight disability. Cannot carry out all previous activities.

3 Moderate disability. Requires some help, but walks unassisted.

4 Moderate severe disability. Cannot attend to own bodily needs or walk without assistance.

5 Severe disability. Requires constant nursing care.

6 Dead

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b. Barthel Index (BI) (Appendix B)

i. Measures ability to perform activities of daily living

ii. Total range 0 [entirely dependent] to 100 [performs self-care and mobility without assistance]

c. Glasgow Outcome Scale (GOS) (Appendix C)

i. Assesses broad outcomes after acute brain injury

ii. Total range 1 [good recovery] to 5 [death]

d. Oxford Handicap Score (OHS) (Appendix D)

i. Assesses functional ability

ii. Total range 0 [no symptoms] to 5 [death]

iii. Used as alternative to mRS

Guideline Recommendations for Management

I. American Heart Association/American Stroke Association (AHA/ASA)6

a. Goal 60-minute door-to-needle time in patients with AIS

b. 1.9 million neurons destroyed for every minute of delay during MCA occlusion

Figure 5. AIS Treatment Timeline6

II. Diagnosis1,4

a. Initial stroke assessment using NIHSS score

b. Neurovascular imaging

i. Primary imaging goals:

1. Rule out acute cerebral hemorrhage

2. If possible, define ischemic damage and visualize vessel status

ii. Computed tomography (CT)

1. Current standard

2. Quick and widely available

3. Rules out acute cerebral hemorrhage

4. Can identify major ischemic stroke in two-thirds of cases

5. Cytotoxic edema visualized on CT as hypodensity no earlier than 45 minutes after stroke onset

6. Only 40-60% sensitivity within 3 hours after stroke onset

iii. Magnetic resonance imaging (MRI)

1. Higher sensitivity for minor stroke

2. Can detect ischemia within 11 minutes of stroke onset

3. Time-consuming

0 min

•Patient arrives

<10 mins

•MD evaluation

•Lab work

•NIHSS assessment

<15 mins

•Notify stroke team

<25 mins

•Initiate neuro imaging

<45 mins

•Interpret imaging

•Review labs

•Review patient eligibility for tPA

<60 mins

•Give tPA bolus

•Initiate tPA infusion

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Head CT Showing AIS Brain MRI Showing AIS Hemorrhagic Stroke on Head CT

Figure 6. Head Imaging Interpretation

III. Recanalization of infarct-related artery

a. Pharmacological thrombolysis with tissue plasminogen activator (tPA) alteplase

Figure 7. Alteplase Background

6,11,12

i. Hemorrhagic transformation13

1. Bleeding after initial ischemic event

2. sICH is primary safety outcome in most major trials evaluating tPA for ischemic stroke

(a) Varying definitions of sICH; broadly considered neurological decline associated with ICH on

imaging

(i) Studies may set NIHSS parameters for neurological decline, such as increase in NIHSS of

≥1 or ≥4

(ii) Many studies protocolize imaging to screen for ICH at 36-48 hours, but sICH may be

considered up to 7-10 days after tPA

(b) Studies frequently screen for ICH with imaging at 36-48 hours after tPA administration

3. Can occur regardless of thrombolytic treatment, but tPA significantly increases risk9,10,14-16

(a) Median sICH rate from five major IV alteplase clinical trials: 6.9%

(b) Compared to 0.6% in placebo group

FDA Approved Indications

• Acute ischemic stroke

• Acute myocardial infarction

• Acute massive pulmonary embolism

Mechanism of Action

• Binds fibrin in thrombus to convert plasminogen to plasmin

• Induces local fibrinolysis

Ischemic Stroke Dosing

• 0.9 mg/kg (max 90 mg) IV

• 10% bolus over 1 minute

• Remainder infused over 1 hour

Adverse Reactions

• Intracranial hemorrhage (>10%)

• Other hemorrhage: gastrointestinal (5%), genitourinary (4%)

• New ischemic stroke (6%)

• Angioedema (1%)

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4. sICH risk may be associated with stroke severity

(a) Correlation with size of ischemic lesion17

(i) Diffusion-weighted MRI to identify areas of severe ischemic damage; lesions categorized

by volume

(ii) 2.1% sICH in very small lesions (≤10 mL)

(iii) 12.8% sICH in large lesions involving more than one-third of MCA territory (>100 mL)

(iv) Used several definitions of sICH; lesion size remained independent predictor of sICH

(b) Correlation with NIHSS score18

(i) 0-2.6% in NIHSS ≤6

(ii) 8.1% in NIHSS >6

Table 3. Evidence for tPA in Ischemic Stroke

Study Intervention Results

Tissue Plasminogen Activator for Acute

Ischemic Stroke (NINDS) 1995

9

tPA 0.9 mg/kg IV vs. placebo within 3 hours of onset

No difference in complete resolution/improvement of NIHSS: 47% vs 39% (p=0.21)

tPA group more favorable 90-day outcomes (p=0.008)

No difference in 90-day mortality (p=0.30)

tPA group higher sICH rate: 6.4% vs 0.6% (p<0.001)

Thrombolysis with Alteplase 3 to 4.5 Hours

After Acute Ischemic Stroke (ECASS III)

200810

tPA 0.9 mg/kg vs. placebo 3-4.5

hours after onset

tPA group more favorable 90-day outcomes (mRS 0-1): 52.4% vs 45.2% (p=0.04)

tPA group significantly more sICH: 2.4% vs 0.2% (p=0.008)

No difference in 90-day mortality (p=0.68)

Benefits and Harms of IV Thrombolysis with

Recombinant tPA Within 6 Hours of Acute Ischemic Stroke (IST-3)

201214

tPA 0.9 mg/kg vs. placebo within 6 hours of onset

More patients in tPA group alive and independent (OHS 0-2) at 6 months: 37% vs 35% (p<0.001)

tPA group higher mortality within 7 days: 11% vs 7% (p=0.0004)

tPA group lower mortality beyond 7 days: 16% vs 20% (p=0.002)

Greatest benefit in patients treated within 3 hours and with more severe strokes

ii. Determining patient eligibility for tPA requires weighing bleeding risk against potential benefit

1. Many eligibility criteria are based on NINDS and ECASS III exclusions

Table 4. Contraindications to Thrombolysis6

Absolute Relative 3-4.5 Hours Only

Current ICH or subarachnoid hemorrhage

Intracranial/intraspinal surgery within 3 months

Age >80 years oldψ

Active internal bleeding Ischemic stroke within 3 months DM and prior stroke historyψ

Platelets <100,000 ICH history NIHSS Score >25

Anticoagulation

LMWH within 24 hours

FXa or DTI within 48 hoursϨ

Warfarin with INR >1.7

GI malignancy or GI bleed within 21 days

Oral anticoagulationτ

Current uncontrolled hypertension Major trauma (not involving head) within 14 days

Involvement of >1/3 MCA territory

ϨtPA may be reasonable if aPTT, INR and other appropriate assays are normal

ψIV tPA may be as effective in 3-4.5 hour window as 0-3 hours; may be reasonable to treat

τIV tPA may be safe and beneficial in patients taking warfarin with INR <1.7

LMWH: low molecular weight heparin, FXa: Factor Xa inhibitor, DTI: direct thrombin inhibitor

Jaeger 9

b. Endovascular therapy6

i. Potential intervention after tPA administration or an alternative when tPA is contraindicated

ii. Must meet certain criteria to be eligible, including but not limited to:

1. Prestroke mRS 0-1

2. Occlusion of ICA or MCA

3. NIHSS score ≥6

4. Able to initiate within 6 hours of stroke onset

iii. Should not be delayed to assess tPA response; decreased time to arterial puncture improves outcomes

Mild Stroke

I. Background

a. Definition19

i. No consensus definition exists

ii. Traditional cutoff in major trials is NIHSS ≤5

iii. Other suggested definitions

1. Score of 0-1 on every NIHSS component and a 0 only on consciousness questions

2. Baseline NIHSS ≤3

b. NIHSS may not accurately discriminate between minor and non-minor strokes19,20

i. Can have disabling symptoms despite low NIHSS score

1. Does not capture some stroke signs such as gait, balance, and hand function

2. More heavily weighted for anterior stroke symptoms vs posterior21,22

ii. In patients with NIHSS ≤4, 65% had language impairment, 37% had distal paresis, 29% had gait disorder

II. Strokes with NIHSS ≤5 account for half of AIS in the United States23

III. Mild stroke excluded in many major tPA trials9,10,14

a. NINDS and ECASS III explicitly excluded patients with minor or rapidly improving symptoms

i. Despite exclusion criteria, inadvertently enrolled 58 and 128 patients with NIHSS 0-5, respectively

ii. NINDS enrolled no patients with isolated motor symptoms, facial droop, ataxia, dysarthria, sensory

symptoms, or NIHSS 0

b. IST-3 enrolled 612 patients with NIHSS 0-5; only 106 had no other standard exclusion criteria

IV. AHA/ASA recommendations for management of mild stroke are not definitive

Figure 8. AHA/ASA Guideline Recommendations for Treatment of Mild Stroke6

Patients with mild but disabling stroke symptoms should NOT be excluded from treatment with tPA

“Proven clinical benefit” for these patients

Treatment of non-disabling symptoms may be considered

<3 hours

For otherwise eligible patients, tPA treatment may be reasonable

Treatment risks should be weighed against potential benefits

3-4.5 hours

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V. Patients with mild stroke are less likely to receive tPA treatment

a. Between 31-36% ischemic stroke patients do not receive tPA solely due to a mild stroke diagnosis24,25

b. Despite minor symptoms, many patients with mild ischemic stroke have poor outcomes

LTAC: long-term acute care, SNF: skilled nursing facility

Figure 9. Outcomes of Mild Stroke Not Treated with tPA26-30

VI. Potential causes of disability at 90 days after a mild stroke31

a. Deficits uncaptured or underappreciated by NIHSS

b. Recurrent stroke

c. Early neurologic deterioration (END)32-34

i. Affects 7-13% of AIS patients

ii. No consensus definition

1. Neurologic worsening, including consciousness level, within 48-72 hours of stroke

(a) Underlying mechanisms within 48-72 hours are likely still neurologic

(b) May still be considered END up to 5 days after stroke

2. Some studies set quantitative parameters, such as NIHSS increase of ≥2

iii. Associated with 17% mortality prior to discharge

iv. Mechanisms of END33

1. Collateral failure: most common35

(a) Inadequate collaterals: 4 times greater worsening rate

(b) No difference in in-hospital worsening for patients with proximal MCA occlusion with

adequate collaterals compared to patients with no occlusion

2. Clot progression

3. Recurrent stroke: highest risk in first week following AIS

4. Cerebral edema

5. Hemorrhagic transformation

6. Re-occlusion of recanalized artery: occurs in 34% of tPA-treated patients

v. No drug, including alteplase, has demonstrated reduced END,

vi. Antiplatelet agents protect against recurrent cerebral ischemia

VII. Possible predictors of unfavorable outcomes in patients with mild stroke

a. Independent risk factors for poor outcomes in untreated stroke28,36

:

i. Aphasia

ii. Older age

iii. Hispanic ethnicity

iv. Diabetes mellitus

v. Posterior circulation involvement

b. Diabetes, higher baseline NIHSS, and deep MCA infarction are predictors of poor outcome despite treatment37

i. Diabetes: elevated levels of plasminogen activator inhibitor poor response to thrombolysis

28-32% discharged to LTAC or SNF

28% cannot walk independently at

discharge

29-38% have mRS 2-6 at 90 days

Jaeger 11

Evidence for tPA in Mild Stroke

Table 5. You S, Saxena A, Wang X, et al. Efficacy and safety of intravenous recombinant tissue plasminogen activator in mild ischemic stroke: a meta-analysis. Stroke Vasc Neurol. 2018;3:22-27.

38

Objective

Evaluate tPA efficacy and safety in mild AIS

Methods

n=1591

Meta-analysis of seven studies: five prospective cohort studies and two post hoc analyses from large clinical trials

Study Inclusion

Inclusion

NIHSS ≤6

Compared tPA vs not treated

Defined favorable outcome as mRS 0-1 or OHS 0-1

Provided data on sICH and mortality at 3 or 6 months

Symptom onset to needle time <4.5 hours

Exclusion

No comparator group

Excellent outcome evaluated on hospital discharge

Incomplete data for subgroups

Outcomes Evaluated

Excellent functional outcome (mRS 0-1 or OHS 0-1)

sICH

90-day mortality

Results

Outcome tPA group (n=801) Placebo group (n=790) P-value I2

mRS 0-1 or OHS 0-1 74.8% 67.6% 0.002 35%

sICH 1.87% 0% 0.006 0%

Mortality 2.4% 2.9% 0.43 0%

Authors’ Conclusions

Rate of unfavorable outcomes is high in mild stroke

Pooled analysis suggests more favorable outcomes in patients who receive tPA

tPA associated with increased rate of sICH o Lower than rate of sICH reported in treated patients with more severe stroke o sICH did not contributed to increased mortality in tPA group

Reviewer’s Critique

Strengths

Reasonable level of heterogeneity for all evaluated outcomes

All studies included a comparator group

Limitations

Single centers, small number of patients

No randomized controlled trials

Little data about type and location of stroke

Could not report adjusted OR

Definition of sICH varied

Selection of treatment group biased; baseline NIHSS significantly higher in several studies

Conclusion

In mild stroke with NIHSS ≤6, tPA improves outcomes at 90 days while also increasing sICH risk.

Clinical Question #1: In mild stroke, do potential benefits of tPA outweigh risk of hemorrhagic transformation?

Jaeger 12

I. Take-home points

a. Individual studies underpowered to detect difference in outcomes or sICH rate, but pooled analysis

demonstrates tPA improves functional outcomes at 90 days in patients with NIHSS ≤6

b. tPA benefit may have been greater if groups had comparable baseline NIHSS

c. tPA increases sICH risk in mild stroke but rates are lower than in more severe strokes

Table 6. Results of You et al. Included Studies (tPA vs no tPA)

Author (Year) (n) Mild

NIHSS

Time to

Needle (Hrs)

Baseline NIHSS, median

(IQR)

mRS 0-1 at 3mos or

OHS 0-1 at 6 mos

sICH Mortality at

3 mos Note/Other Outcomes

Khatri et al.,39

2010

58 ≤5 <3 Both

groups: 4 (4)

78% vs 81%

1.7% vs 0%

NR

NINDS post hoc analysis

Huisa et al.,40

2012

133 ≤5 <3 4 (2.5-5)

vs 2 (1-2)Ϯ

58% vs 69%

5% vs NR

5.1% vs 4.1%

Urra et al.,41

2013

203 ≤5 <4.5 3 (2-4)

vs 2 (1-3.8)Ϯ

83% vs 81%

0% vs 0%

1.7% vs 3.6%

tPA associated with favorable mRS shift at 90 days

Greisenegger et al.,

42 2014

890 ≤5 <3 Both

groups: 4 (3-5)

68% vs NR

2.5% vs 0%

NR

Benefit driven by patients with NIHSS 4-5; NS for those with NIHSS <4

Nesi et al.,36

2014

128 ≤6 <3 n/a 83% vs 87%

0% vs 0%

0% vs 0%

tPA more beneficial in patients with aphasia

Khatri et al.,43

2015

106 ≤5 <3 Both

groups: 4

60% vs 51%

0% vs 0%

NR

IST-3 post hoc analysis

Favorable shift in OHS at 6 months in tPA group

Ng et al.,44

2016

73 ≤3 <4.5 Overall: 2

(1-3)

91% vs 72%

0% vs 0%

NR

Favorable mRS shift in tPA group at discharge and 90 days

No difference in LOS or ability to be discharged home

Meta-analysis Results

Pooled Analysis

1591 ≤6 <4.5 NR 75% vs 68%

1.9% vs 0%

2.4% vs 2.9%

= NS difference;

Ϯ = significant difference in baseline NIHSS; = tPA significantly better; = tPA significantly worse

Jaeger 13

Evidence for tPA in Mild Stroke with Non-disabling Deficits

Table 7. Spokoyny I, Raman R, Ernstrom K, et al. Defining mild stroke: outcomes analysis of treated and untreated mild stroke patients. J Stroke Cerebrovasc Dis. 2015;24(6):1276-81.

45

Objective

Compare patients treated and untreated with tPA using two definitions of mild stroke

Methods

n=1085

Exploratory study of prospective stroke registry

Patients grouped by baseline mRS and definition of “mild” o Definition 1: NIHSS 0-5, regardless of specific symptoms o Definition 2: NIHSS 0-5 and absence of any TREAT-defined disabling stroke symptoms (full criteria in Appendix E)

Four patient groups: o Group 1: baseline mRS 0 + mild defined NIHSS 0-5 o Group 2: baseline mRS 0 + TREAT-derived mild definition o Group 3: any baseline mRS + mild defined NIHSS 0-5 o Group 4: any baseline mRS + TREAT-derived mild definition

Subgroup patient analysis of patients deemed “too mild to treat” (TMT) by clinician

Patient Population

Inclusion

Mild stroke treated or not treated with tPA

Exclusion

Mechanical treatment or other therapies received

Outcomes Evaluated

Dichotomized mRS at 90 days (0-1 or 2-6)

sICH

Baseline Characteristics

Treated vs Untreated (Groups 1 & 2)

Treated group had higher baseline NIHSS o Group 1: 3.45 vs 2 (p<0.0001) o Group 2: 3.29 vs 1.81 (p<0.0001)

TMT vs Other Untreated (Groups 1 & 2)

TMT (including patients with TMT as only exclusion criteria) had lower baseline NIHSS

o Group 1: 1.65 vs 2.61 (p<0.0001) o Group 2: 1.49 vs 2.33 (p=0.0013)

Results

Group 1 (n=276) Group 2 (n=184) Group 3 (n=374) Group 4 (n=251)

Mild Definition NIHSS 0-5 TREAT NIHSS 0-5 TREAT

Poor Outcome at 90 Days

Treated vs Untreated 37.4 vs 31.1%

(p=0.44) 35.6 vs 28.8%

(p=0.47) 38.1 vs 32.3%

(p=0.67) 32.8 vs 29%

(p=0.47)

TMT vs Rest of Untreated

29.2 vs 33.8% (p=0.48)

25.3 vs 34.6% (p=0.95)

29.7 vs 36% (p=0.95)

26 vs 34.3% (p=0.59)

TMT Only vs Treated 25 vs 37.35%

(p=0.67) 15.2 vs 35.6%

(p=0.28) 29.8 vs 38.1%

(p=0.72) 21.7 vs 32.8%

(p=0.96)

sICH (among treated) 0 0 3 (2.9%) 2 (4%)

Authors’ Conclusions

No difference in outcomes between treated and untreated mild stroke patients, regardless of definition of “mild” stroke

25-30% of patients with mild stroke, treated or untreated, will have poor outcomes at 90 days

Definitive conclusion cannot be made due to selection bias; treated patients had higher baseline NIHSS

Clinical Question #2: Does tPA benefit outweigh sICH risk in mild ischemic stroke if deficits are non-disabling?

Jaeger 14

Reviewer’s Critique

Strengths

Limited selection bias by separating groups into patients with baseline mRS 0 vs any mRS

Used two definitions of mild stroke

Limitations

Untreated group included patients arriving >3 hours after onset

Treated patients had higher baseline NIHSS

Conclusion

Patients deemed too mild to treat with non-disabling deficits and no other standard thrombolysis exclusion criteria do not benefit from tPA and may have better outcomes than other mild stroke patients.

I. Take-home points

a. Very few conclusions can be made due to study design

b. Low risk of sICH in mild stroke, especially with baseline mRS 0

c. TMT patients with non-disabling deficits (TREAT-derived criteria group) had lower rates of poor outcome than

previously reported for mild stroke

d. Can likely exclude patients with non-disabling deficits from tPA treatment

Table 8. Khatri P, Kleindorfer DO, Devlin T, et al. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor non-disabling neurologic deficits: the PRISMS randomized clinical trial. JAMA. 2018;320(2):156-166.

46

Objective

Evaluate tPA efficacy and safety compared to aspirin in patients with NIHSS 0-5 and non-disabling deficits

Methods

n=313

Phase 3b, multicenter, randomized, double-blind clinical trial testing safety and efficacy of IV tPA administered within 3 hours of symptom onset vs aspirin

Intervention

IV alteplase 0.9 mg/kg (to be administered within 3 hours of stroke onset)

Oral aspirin 325 mg (to be administered within 24 hours of stroke onset)

Patient Population

Inclusion

AIS diagnosis

NIHSS 0-5

Deficits at presentation not clearly disabling o “Clearly disabling”: prevents performance of basic

activities of daily living or returning to work

Exclusion

Pre-stroke mRS 2-6

Dysphagia

Intracranial hemorrhage on neuroimaging

Other standard contraindications to tPA as reflected by guidelines

Outcomes Evaluated

Primary

mRS of 0-1 at 90 days (adjusted for age, time from symptom onset to treatment, and baseline NIHSS) Secondary

Level of disability, assessed by mRS

Global favorable recovery: mRS 0-1, NIHSS 0-1, BI 95-100, and GOS score of 1 Primary Safety

sICH: any neurologic decline within 36 hours attributed to ICH by local investigators

Statistics

Necessary sample size calculated to be 856 participants, increased to 948 to account for dilution of treatment effect associated with nonadherence

Ended early prior to database lock and without unblinding due to patient recruitment below target

Post hoc analysis: o Likelihood of any alteplase benefit o Likelihood of absolute benefit of >6%

Jaeger 15

Baseline Characteristics

Characteristic tPA Group (n=156) Aspirin Group (n=157)

Time from symptom onset to oral study treatment, median (IQR), h

2.7 (2.2-2.9) 2.6 (2.1-2.9)

Baseline NIHSS score, n (%)

0 7 (4.5) 7 (4.5)

1 38 (24.4) 50 (31.8)

2 52 (33.3) 50 (31.8)

3 32 (20.5) 30 (19.1)

4 21 (13.5) 16 (10.2)

5 6 (3.8) 4 (2.5)

Mean (SD) 2.1 (1.2) 2.0 (1.2)

Results

Outcome tPA Group Aspirin Group Risk Difference or OR

mRS score 0-1, adjusted, n (%) 122 (78.2) 128 (81.5) -1.1 [(-9.4)-7.3]

mRS score distribution at 90 days, n (%) OR, 0.81 (0.5-1.2)

0 70 (44.9) 79 (50.3)

1 52 (33.3) 49 (31.2)

2 18 (11.5) 18 (11.5)

3 4 (2.6) 5 (3.2)

4 8 (5.1) 4 (2.5)

5-6 4 (2.6) 2 (1.3)

Global favorable recovery OR, 0.86 (0.5-1.4)

sICH within 36 hours, n (%) 5 (3.2) 0 3.3 (0.8-7.4)

281 (89.8%) completed trial’s primary outcome assessment

Overall, 19% had mRS score 2-6 at 90 days

Post hoc analysis, probability that tPA would improve favorable outcomes: o To any degree: 23%; By 6%: 1.9

Authors’ Conclusions

Patients with mild, non-disabling stroke treated with tPA did not have improved outcomes compared to patients treated with aspirin

19% rate of mRS 2-6 at 90 days lower than previously observed 30%, potentially due to baseline non-disabling deficits definition and because aspirin patients got early administration (75% within 3.1 hours)

tPA increases sICH risk, but slightly lower than rate reported in studies of more severe stroke treated with tPA

sICH was not associated with increased mortality

Reviewer’s Critique

Strengths

Prospective, randomized, with comparator

Groups well-matched

Limitations

Early trial termination and underpowered (30% power)

Subjective definition of “not clearly disabling”

Relatively high loss to follow-up at 90 days

Non-disabling requirement essentially same as favorable outcome mRS 0-1

Conclusion

tPA does not improve outcomes compared to aspirin in patients with mild, non-disabling ischemic stroke.

I. Take-home points

a. Due to study design, tPA would have to prevent deterioration to show a difference compared to aspirin

b. Most patients with “unfavorable outcome” at 90 days had mRS 2, which correlates with only slight disability

c. Poor outcome rate lower than reported in previous studies of untreated mild stroke

d. Aspirin is likely sufficient treatment for mild stroke patients with non-disabling deficits

Jaeger 16

Summary and Recommendations

I. Summary

a. Mild stroke excluded from many major tPA trials

i. sICH risk

ii. Possibility of spontaneous resolution of symptoms

b. Patients with mild stroke (NIHSS ≤5) at significant risk of poor functional outcome at discharge and 90 days

c. Lack of prospective, randomized controlled trials limits ability to determine tPA safety and efficacy in mild stroke

i. In pooled analysis, tPA-treated had more favorable outcomes at 90 days than untreated

ii. Individual studies in the meta-analysis found significant shift in mRS at 90 days

iii. tPA increases sICH risk; however, sICH rate in mild stroke is lower than rate reported in more severe stroke

d. Unlikely that tPA benefits outweigh sICH risk in mild, non-disabling stroke

II. Treatment recommendations

a. No clear definition of “disabling” deficits; determination of stroke as disabling vs non-disabling should be left to

physician and patient discretion

b. Patients with NIHSS ≤5 and disabling symptoms should receive tPA when:

i. No other contraindications to tPA treatment

ii. Can be administered within 4.5 hours of symptom onset

c. Patients with NIHSS ≤5 and non-disabling symptoms can be managed with expeditious administration of aspirin

(first dose ideally within 3 hours) and close monitoring

Future Directions

I. Ongoing clinical trials with alteplase

a. ARAMIS trial: Antiplatelet vs R-tPA for Acute Mild Ischemic Stroke47

i. Randomized, parallel assignment, open label

ii. Interventions

1. Aspirin 100 mg daily + clopidogrel 75 mg daily (first dose 300 mg) for 10-14 days, then aspirin 100 mg

or clopidogrel 75 mg for 90 days

2. IV alteplase 0.9 mg/kg followed by antiplatelet 24 hours after thrombolysis

iii. Inclusion: NIHSS score ≤5 overall and ≤1 in single item scores, treatment within 4.5 hours of onset

iv. Primary outcome: mRS 0-1 at 90 days

II. Tenecteplase48

a. Does not currently have FDA approval for ischemic stroke, but is first-line IV thrombolytic for myocardial

infarction

b. Has higher affinity for fibrin and longer half-life than alteplase

c. May have higher recanalization rates and is as safe as alteplase

d. TEMPO-2 trial: A Randomized Controlled Trial of TNK-tPA Versus Standard of Care for Minor Ischemic Stroke with

Proven Occlusion49

i. Multicenter, prospective, randomized, open label, blinded endpoint, controlled trial

ii. Interventions

1. IV tenecteplase 0.25 mg/kg

2. Aspirin or aspirin plus clopidogrel (clinician’s discretion)

iii. Inclusion: transient ischemic attack or minor stroke with NIHSS ≤5, presenting within 12 hours of onset

iv. Primary outcome: mRS at 90 days

Jaeger 17

Appendices

Appendix A.

National Institutes of Health Stroke Scale Score (NIHSS)50

Category Score

1. Level of Consciousness 0=Alert; keenly responsive 1=Not alert, but arousable by minor stimulation 2=Not alert; requires repeated stimulation 3=Unresponsive or responds with only reflex

1b. Level of consciousness questions: What is the month? What is your age?

0=Answers two questions correctly 1=Answers one question correctly 2=Answers neither questions correctly

1c. Level of consciousness commands: Open and close your eyes. Grip and release your hand.

0=Performs both tasks correctly 1=Performs one task correctly 2=Performs neither task correctly

2. Best gaze 0=Normal 1=Partial gaze palsy 2=Forced deviation

3. Visual 0=No visual loss 1=Partial hemianopia 2=Complete hemianopia 3=Bilateral hemianopia

4. Facial palsy 0=Normal symmetric movements 1=Minor paralysis 2=Partial paralysis 3=Complete paralysis of one or both sides

5. Motor arm 5a. Left arm 5b. Right arm

0=No drift 1=Drift 2=Some effort against gravity 3=No effort against gravity 4=No movement

6. Motor leg 6a. Left leg 6b. Right leg

0=No drift 1=Drift 2=Some effort against gravity 3=No effort against gravity 4=No movement

7. Limb ataxia 0=Absent 1=Present in one limb 2=Present in two limbs

8. Sensory 0=Normal; no sensory loss 1=Mild-to-moderate sensory loss 2=Severe to total sensory loss

9. Best language 0=No aphasia; normal 1=Mild to moderate aphasia 2=Severe aphasia 3=Mute, global aphasia

10. Dysarthria 0=Normal 1=Mild to moderate dysarthria 2=Severe dysarthria

11. Extinction and inattention 0=No abnormality 1=Visual, tactile, auditory, spatial, or personal inattention 2=Profound hemi-inattention or extinction

Jaeger 18

Appendix B.

Barthel Index8

Category Score

Feeding 0=Unable 5=Needs help cutting, spreading butter, etc., or requires modified diet 10=Independent

Bathing 0=Dependent 5=Independent

Grooming 0=Needs help with personal care 5=Independent (face/hair/teeth/shaving)

Dressing 0=Dependent 5=Needs help but can do about half unaided 10=Independent (including buttons, zips, laces, etc.)

Bowels 0=Incontinent (or needs to be given enemas) 5=Occasional accident 10=Continent

Bladder 0=Incontinent, or catheterized and unable to manage alone 5=Occasional accident 10=Continent

Toilet Use 0=Dependent 5=Needs some help, but can do some things alone 10=Independent (on and off, wiping, dressing)

Transfers (bed to chair and back)

0=Unable, no sitting balance 5=Major help (one or two people, physical), can sit 10=Minor help (verbal or physical) 15=Independent

Appendix C.

Glasgow Outcome Scale8

Score Definition

5 (Good outcome) Resumes normal life; may have minor neurological and/or psychological deficits

4 (Moderate disabled) Able to work in sheltered environment and travel by public transportation

3 (Severely disabled) Dependent for daily support due to mental or physical disability or both

2 (Persistent vegetative state) Unresponsive and speechless for weeks, months, or until death

1 (Death) Death

Appendix D.

Oxford Handicap Score51

Grade Handicap Lifestyle

0 None No change

1 Minor symptoms No interference

2 Minor handicap Some restrictions but can look after self

3 Moderate handicap Significant restriction; unable to lead independent life; requires some attention

4 Moderate-to-severe handicap Unable to live independently but does not require constant attention

5 Severe handicap Totally dependent; requires constant attention day and night

Appendix E.

TREAT-derived Mild Stroke Criteria45

NIHSS 0-5 and the absence of any of the following:

Complete hemianopia

Severe aphasia

Visual or sensory extinction

Any weakness limiting sustained effort against gravity

Any deficit considered potentially disabling in patient or practitioner’s opinion

Jaeger 19

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