Acute Ischemic Stroke (AIS) & IV tPA

 Integrative Health Policy

College of Human MedicineMichigan State University

April 4, 2012 

Zach Jarou, Juan Rango, Nate Harris, Samantha Shaw, Eric Bracken, Nakia Hunter, Ahmed Hozain, Danielle Chang

US Stroke Burden: Mortality

● 3rd leading cause of mortality in US  

● 1 out of every 18 deaths 

● one stroke death every 4 minutes 

● nearly 1 out of 10 45-65 year old patients die within 30 days

(AHA 2011)

US Stroke Burden: Disability

● mortality aside, strokes are the leading cause of severe, long-term adult disability

 ● Framingham Heart Study

○ AIS survivors, 65+ yo, 6 months after event

○ 50% = some evidence of hemiparesis

○ 30% = unable to walk without assistance

○ 19% = aphasia

○ 26% = institutionalized (Wechsler 2011)

US Stroke Financial Burden: Costs (2007)

● total = $40.9 billion○ direct (medical)

= $25.2 billion○ indirect

= $15.7 billion 

● mean lifetime cost of AIS ~$140,048

(AHA 2011, Image from Scientific American)

US Stroke Burden: Incidence

● new stroke case every 40 seconds ● ~795,000 cases per year in total

○ 610,000 first attacks; 185,000 recurrent

 ● 87% are ischemic (in situ thrombosis,

embolism, systemic hypoperfusion)○ 10% intracerebral hemorrhage

○ 3% subarachnoid hemorrhage

  (AHA 2011)

Treatment: A Unique Opportunity

strokes are the only neurologic disorder for which physicians are potentially able to completely reverse disabling deficits (Lyden 2008) 

Current Use of tPA for AIS

● Currently, only 1-8% of all AIS patients are treated with tPA

 ● first approved by FDA in 1996 for treatment

of AIS within 3 hours of symptom onset based on results of NINDS study

 

● contraindicated in hemorrhagic strokes or head trauma

 (Huisa 2011)

Risk of tPA Use = symptomatic ICH

● Usually occur within 24-36h after thrombolysis (ICH after 36h considered unrelated to tPA)

● Typically occurs in the core of the infarction (suggests ischemia itself plays a role)

● NINDS sICH rates○ tPA = 6.4%, placebo = 0.6%○ sICH mortality rate = 47%○ mortality rate still lower in tPA group compared to

placebo group (17% vs. 21%) due to reduction in death not related to hemorrhage

(Derex 2008)

Risk of tPA Use = symptomatic ICH

● sICH risk factors○ longer onset-to-treatment○ dosing○ age

■ >80 yo = 3x risk of sICH■ >90 yo = 2x risk sICH/mortality of 80 yo

○ hypertension (during first 24 hours)○ hyperglycemia

■ >200mg/dL = increased risk (25% sICH rate)■ >400mg/dL = contraindication

  (Derex 2008)

Risk of tPA Use = symptomatic ICH

● sICH risk factors (continued)○ severe stroke (NIHSS score > 20 = 11x risk)○ early CT changes (4x risk if EIC > than 1/3 MCA)○ moderate to severe leukoaraiosis (white matter

hyperdensities on imaging not related to any specific pathology) on MRI (OR 2.9)

○ previous anticoagulant therapy■ antiplatelets (Hallevi 2008)

● 1.9 OR sICH, yet still associated w/2 OR favorable outcome

■ warfarin (Parbhakaran 2010)● 10x risk despite INR < 1.7

  

(Derex 2008)

Our Positions (tPA for AIS)

1. increase public education○ risk factors & warning signs○ time-sensitive treatment window 

2. support allowing tPA administration for AISup to 4.5 hours after onset of symptoms if eligibility criteria met

 

Position #1 = Public Education

Position #1 = Public Education

● delay in seeking medical attention after AIS is the most important reason for low rates of tPA use (excludes up to 73% of patients)

 

● ~1/3 people can not name a single risk factor or warning sign of a stroke

 

● only 9% of surveyed patients aware of time-sensitive treatment window from onset of stroke symptoms

  (Barber 2001, Kleindorfer 2009)

Position #2 = Allow Up To 4.5 Hours

● NINDS (1995)○ first study to show efficacy of tPA for AIS when

administered in less than 3 hours○ no difference at 24 hours but treatment group

showed benefit at 90 days (OR = 1.7)● ECASS III (2008)

○ verified NINDS, also demonstrated efficacy between 3-4.5 hours (OR = 1.3)

● Smaller studies will also be mentioned in terms of pooled analysis

Similarities - NINDS & ECASS III

● both are randomized, placebo-controlled trials showing favorable outcomes at 90 days post-tPA treatment using a modified Rankin Scale of disability (0 = none, 6 = death), favorable outcome = mRS 0 or 1

 ● both excluded patients with mild or rapidly

improving strokes yet failed to clearly define this threshold in terms of NIHSS scores

  (Huisa 2011)

Differences = NINDS & ECASS III

● NINDS = broad generalizability ○ included all patients >18 years old

 ● ECASS III = limited generalizability,

excluded:○ >80 years old○ severe stroke

(NIHSS > 25 or hypodensity of >1/3 MCA on CT)○ those taking anticoagulants (regardless of INR)○ history of both stroke and diabetes

 

Have other studies supported the 4.5-hour ECASS III cutoff window?

● Alone No, Pooled YES! (Lansberg, July 2009)○ allowed tPA up to 6 hours after stroke onset○ only 14% were treated within 3 hours

● Pooling doubles the available sample size between 3-4.5 hours (from 821 to 1622)

● Pooled OR the same as ECASS III OR (1.3)

Have other studies supported the 4.5-hour ECASS III cutoff window?

● On their own, ECASS I, ECASS II, & ATLANTIS have wide confidence intervals and high p-values

● Pooled analysis yields similar OR as ECASS III alone but with a smaller p-value

 

Timing is everything!

Saver 2010

=ECASS III data should

not suggest a leisurely approach

to tPA administration,

every minute counts (Leyden 2008)

Timing is everything!

OTT NNT NNH0 to 1.5 hrs 3.6

(3.1-4.2)

65 (38-111)

1.5 to 3 hrs 4.3 (3.6-5.3)

38(24-61)

3 to 4.5 hrs 5.9 (4.3-8.2)

30(20-45)

4.5 to 6 hrs 19.3 (12.0-31.0)

14(10.5-17.8)

< < < >

(Lansberg, June 2009) NNT and NNH are inversely proportional

How Do Our Positions Compare?

● AHA○ 2007 = supported 3 hour window if eligibility criteria met

○ 2009 = added 3-4.5 hour window with additional exclusion criteria 

● AAEM○ 2002 = following NINDS, should not be considered standard of care

given lack of supporting clinical trials ○ 2010 = following ECASS III, acknowledge it is one treatment option

when given in academic centers & primary stroke centers 

● ACEP○ 2002 = endorse use when administered according to NINDS guidelines

(Wechsler 2011)

Alternative Positions

● allow the use of tPA for mild strokes● allow the use of tPA for rapidly improving

strokes ● restrict use of tPA to academic/primary

stroke centers only● no time limit for treatment (buyer beware)

Mild or Rapidly Improving Strokes

● these are the most common, subjective, poorly-defined reasons for non-treatment

 

Smith 2011

1/3 oftime

eligiblepatientsexcluded

tPA for Rapidly Improving Strokes

● initial NINDS draft stated exclusion for rapidly improving "major" symptoms, this qualifier was controversially removed during editing

 

● reanalysis of NINDS using 3 objective definitions for rapid improvement ○ >4 NIHSS points (OR 1.83, 1.22-2.75)○ >25% improvement (OR 2.02, 1.35-3.02)○ >50% improvement (OR 1.99, 1.33-2.97)

 

● favorable treatment effect with all 3 definitions, therefore tPA not contraindicated

ISC Abstracts 2011, #145

tPA for Mild Strokes

● to patients, there's no such thing as a "mild stroke"● disability is very common even w/NIHSS <= 5

○ 28.3% not discharged home○ 28.5% not able to ambulate w/o help at discharge

Smith 2011

tPA for Mild Strokes

● no large studies have been performed to conclusively determine tPA benefit for mild strokes

● if tPA as effective for minor strokes as in serious strokes:○ up to 3700 fewer patients would be disabled○ potential annual disability savings of $200 million

● funding currently being sought for PRISMS trial (Potential of rtPA for Ischemic Strokes with Mild Symptoms)

ISC Abstracts 2011, #47

Restrict Use to Academic &Primary Stroke Centers

● community hospitals may have difficulty accessing neurological expertise and fear of sICH

 

● Neuro consults not associated with decreased protocol compliance; best to avoid Tx delays (Meurer 2010)

 

● deviations from protocols lead to poor outcomes, Cleveland-study:

○ 50% deviation --> 15.7% rate of sICH

○ 19% deviation --> 6.4% rate of sICH (~NINDS)

(Bruce 2011)

Restrict Use to Academic &Primary Stroke Centers

● routing of AIS patients to stroke centers increases tPA administration rates >10%

 

● BUT, are the post-tPA outcomes better?○ retrospective, observational study of outcomes in 4

SE MI EDs over 9 years showed no difference in outcomes (mortality, sICH, functional) when tPA was given without dedicated thrombolytic stroke teams (Scott 2010)

○ telestroke resources are also now available for community hospitals lacking in-house expertise

(Alexandrov 2005)

No Time Limit for tPA Administration

● should we let the buyer beware? NO! first do no harm (lots of evidence for not exceeding 4.5 hour treatment window)

 

● "patient autonomy is not a trump card" 

● "turning physicians into technicians that perform whatever patients wish systematically devalues their expert judgement & the integrity of medicine as a whole"

(Minkoff 2004)

Economics of tPA Use

● Actual cost per dose of tPA: $2200● Net savings to society per dose: $6074

(Johnston 2010)● t-PA treatment results in an incremental cost

savings of $8000 per QALY gained● A 5% increase in tPA use nationwide would

result in: ○ 30,000 more patients/yr receiving this treatment○ Net cost savings of more than $100 million annually(Demaerschalk 2010, Fagan et al 1998)

  

Economics of tPA Use

● tPA vs. thrombectomy (Mayor 2009)○ thrombectomy devices lack efficacy data (only

show recanalization rates, not outcomes in terms of residual disability on mRS)

○ FDA approves devices differently from drugs, must only show safety, not efficacy "least burdensome rule"

○ payments for thrombectomy range from $19,210 to $28,087 (without or with major complications), compared with $8,408 to $15,945 for thrombolytic treatment (without or with major complications)

Legal Aspects of tPA Use

malpractice is a major concern of most physicians,

however most cases related to the use of tPA for AIS are due to failure to

treat, not adverse events such as sICH

(Bruce 2011, Image from lawlorwinston.com)

Ethics of tPA Use: Shared Decisions

● 91% preferred shared decision-making

 

● 93% of patients wished to receive detailed information on risks & benefits of tPA

 

● patient acceptance rates by severity○ 9% = mild stroke○ 87% = moderately severe○ 97% = severe

(Slot 2009, Image from effectivehealthcare.ahrq.gov)

Ethics of tPA Use: Informed Consent

● complex risk-benefit profile should be thoroughly discussed

● surrogate consent may be necessary

● barriers may include ○ time constraints○ intellectual and emotional

factors in an emergency context

○ neurologic deficits○ aphasia

(White-Bateman 2007, Image from artchive.com)

Ethics of tPA Use: Racial-Ethnic Disparities

● less use of EMS, delayed arrivals to ED, longer ED wait times

● less likely to receive tPA for AIS

● increased mortality rates from AIS

● lack awareness of stroke risk factors, warning signs, & need for urgent treatment

(Cruz-Flores 2011, Image from truthbeautynow.com)

Our Positions (tPA for AIS)

1. increase public education○ risk factors & warning signs

○ time-sensitive treatment window 

2. support allowing tPA administration for AISup to 4.5 hours after onset of symptoms if eligibility criteria met

  

Questions?

ReferencesAHA Statistical Update Heart Disease and Stroke Statistics Circulation 2011; 123:e18-e209 Alexandrov et al. Houston Paramedic and Emergency Stroke Treatment and Outcome Study Stroke 2005; 36:1512-1518 Barber et al. Why are stroke patients excluded from TPA therapy? Am amalysis of patient eligibility. Neurology 2001; 56:1015-1020 Bruce NT, Neil WP, Zivin JA. Medico-legal aspects of using tissue plasminogen activator in acute ischemic stroke. Current Treatment Options in Cardiovascular Medicine 2011;13:233-239 Cruz-Flores S, Rabinstein A, Biller J, et al. Racial-ethnic disparities in stroke care: the American experience: a statement for healthcare professionals from the American Heart Associaton/American Stroke Association. Stroke 2011;42:2091-2116 Demaerschalk BM, Hwang H-M, Leung G. Cost analysis review of stroke centers, telestroke, and rt-PA. American Journal of Managed Care 2010;16:537-544

 

Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischemic stroke: an

update. Journal of Neurology, Neurosurgery and Psychiatry 2008;79:1093-1099

 

Huisa et al. Intravenous Tissue Plasminogen Activator for Patients with Minor Ischemic Stroke. Journal of Stroke and Cerebrovascular Diseases 2011;03:009

 

International Stroke Conference Oral Presentations. Stroke 2011; 42:e42-e110

 

Johnston SC. The economic case for new stroke thrombolytics. Stroke 2010;41:S59-S62

 

Kleindorfer et al. Temporal Trends in Public Awareness of Stroke Warning Signs, Risk Factors, and Treatment. Stroke 2009; 40:2502-2506

 

Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a meta-analysis. Stroke 2009;40:2438-2441

 

Lyden P. Thrombolytic therapy for acute stroke – not a moment to lose. New England Journal of Medicine 2008;359:1393-1395

 

Meurer et al. Lack of Association Between Pretreatment Neurology Consultation and Subsequent Protocol Deviation in Tissue Plasminogen Activator-Treated Patients With Stroke. Stroke 2010; 41(9):2098-2101

 

Mayor S. Devices and drugs for stroke: why do regulations differ? Lancet Neurology 2009;8:982-983

 

Minkoff et al. Ethical dimensions of elective primary cesarean delivery. Obstetrics and Gynecology 2004 Feb; 103(2):387-92

 

Scott PA, Frederiksen SM, Kalbfleisch JD, et al. Safety of intravenous thrombolytic use in four emergency departments without acute stroke teams. Academic Emergency Medicine 2010;17:1062-1071

 

Slot et al. Thrombolytic Treatment for Stroke: Patient Preferences for Treatment, Information, and Involvement. Journal of Stroke and Cerebrovascular Diseases 2009;18(1):17-22

 

Smith EE, Fonarow GC, Reeves MJ, et al. Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from Get With the Guidelines-Stroke. Stroke 2011;42:3110-3115

 

Wechsler LR. Intravenous thrombolytic therapy for acute ischemic stroke 2011;364:2138-2146

 

White-Bateman SR, Schumacher C, Sacco RL, et al. Consent for intravenous thrombolysis in acute stroke. Review and future directions. Archives of Neurology 2007;64:785-792

 

ReferencesDemaerschalk BM, Hwang H-M, Leung G. Cost analysis review of stroke centers, telestroke, and rt-PA. American Journal of Managed Care 2010;16:537-544 Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischemic stroke: anupdate. Journal of Neurology, Neurosurgery and Psychiatry 2008;79:1093-1099 Huisa et al. Intravenous Tissue Plasminogen Activator for Patients with Minor Ischemic Stroke. Journal of Stroke and Cerebrovascular Diseases 2011;03:009 International Stroke Conference Oral Presentations. Stroke 2011; 42:e42-e110 Johnston SC. The economic case for new stroke thrombolytics. Stroke 2010;41:S59-S62 Kleindorfer et al. Temporal Trends in Public Awareness of Stroke Warning Signs, Risk Factors, and Treatment. Stroke 2009; 40:2502-2506

 

Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a meta-analysis. Stroke 2009;40:2438-2441

 

Lyden P. Thrombolytic therapy for acute stroke – not a moment to lose. New England Journal of Medicine 2008;359:1393-1395

 

Meurer et al. Lack of Association Between Pretreatment Neurology Consultation and Subsequent Protocol Deviation in Tissue Plasminogen Activator-Treated Patients With Stroke. Stroke 2010; 41(9):2098-2101

 

Mayor S. Devices and drugs for stroke: why do regulations differ? Lancet Neurology 2009;8:982-983

 

Minkoff et al. Ethical dimensions of elective primary cesarean delivery. Obstetrics and Gynecology 2004 Feb; 103(2):387-92

 

Scott PA, Frederiksen SM, Kalbfleisch JD, et al. Safety of intravenous thrombolytic use in four emergency departments without acute stroke teams. Academic Emergency Medicine 2010;17:1062-1071

 

Slot et al. Thrombolytic Treatment for Stroke: Patient Preferences for Treatment, Information, and Involvement. Journal of Stroke and Cerebrovascular Diseases 2009;18(1):17-22

 

Smith EE, Fonarow GC, Reeves MJ, et al. Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from Get With the Guidelines-Stroke. Stroke 2011;42:3110-3115

 

Wechsler LR. Intravenous thrombolytic therapy for acute ischemic stroke 2011;364:2138-2146

 

White-Bateman SR, Schumacher C, Sacco RL, et al. Consent for intravenous thrombolysis in acute stroke. Review and future directions. Archives of Neurology 2007;64:785-792

 

ReferencesKleindorfer et al. Temporal Trends in Public Awareness of Stroke Warning Signs, Risk Factors, and Treatment. Stroke 2009; 40:2502-2506 Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a meta-analysis. Stroke 2009;40:2438-2441 Lyden P. Thrombolytic therapy for acute stroke – not a moment to lose. New England Journal of Medicine 2008;359:1393-1395 Meurer et al. Lack of Association Between Pretreatment Neurology Consultation and Subsequent Protocol Deviation in Tissue Plasminogen Activator-Treated Patients With Stroke. Stroke 2010; 41(9):2098-2101 Mayor S. Devices and drugs for stroke: why do regulations differ? Lancet Neurology 2009;8:982-983 

ReferencesMinkoff et al. Ethical dimensions of elective primary cesarean delivery. Obstetrics and Gynecology 2004 Feb; 103(2):387-92 Scott PA, Frederiksen SM, Kalbfleisch JD, et al. Safety of intravenous thrombolytic use in four emergency departments without acute stroke teams. Academic Emergency Medicine 2010;17:1062-1071 Slot et al. Thrombolytic Treatment for Stroke: Patient Preferences for Treatment, Information, and Involvement. Journal of Stroke and Cerebrovascular Diseases 2009;18(1):17-22 Smith EE, Fonarow GC, Reeves MJ, et al. Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from Get With the Guidelines-Stroke. Stroke 2011;42:3110-3115 

References Wechsler LR. Intravenous thrombolytic therapy for acute ischemic stroke 2011;364:2138-2146 White-Bateman SR, Schumacher C, Sacco RL, et al. Consent for intravenous thrombolysis in acute stroke. Review and future directions. Archives of Neurology 2007;64:785-792