1. Acute Ischemic
Stroke (AIS) & IV tPA
Integrative Health Policy
College of Human Medicine
Michigan State University
April 4, 2012
Zach Jarou, Juan Rango, Nate Harris, Samantha Shaw,
Eric Bracken, Nakia Hunter, Ahmed Hozain, Danielle Chang

2. 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)

3. 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)

4. 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)

5. 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)

6. Treatment: A Unique Opportunity
strokes are the only neurologic
disorder for which physicians are
potentially able to completely reverse
disabling deficits (Lyden 2008)

7. 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)

8. 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)

9. 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)

10. 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)

11. Our Positions (tPA for AIS)
1. increase public education
○ risk factors & warning signs
○ time-sensitive treatment window
2. support allowing tPA administration for AIS
up to 4.5 hours after onset of symptoms if
eligibility criteria met

12. Position #1 = Public Education

13. 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)

14. 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

15. 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)

16. 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

17. 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)

18. 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

19. Timing is everything!
=
ECASS III data should
not suggest a
leisurely approach
to tPA
administration,
every minute counts
(Leyden 2008)
Saver 2010

20. (Lansberg, June 2009) NNT and NNH
are inversely
Timing is everything! proportional
OTT NNT NNH
0 to 1.5 hrs 3.6 < 65
(3.1-4.2) (38-111)
1.5 to 3 hrs 4.3 < 38
(3.6-5.3) (24-61)
3 to 4.5 hrs 5.9 < 30
(4.3-8.2) (20-45)
4.5 to 6 hrs 19.3 > 14
(12.0-31.0) (10.5-17.8)

21. 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)

22. 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)

23. Mild or Rapidly Improving Strokes
● these are the most common, subjective, poorly-
defined reasons for non-treatment
1/3 of
time
eligible
patients
excluded
Smith 2011

24. 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

25. 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

26. 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

27. 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)

28. 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)

29. 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)

30. 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)

31. 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)

32. 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)

33. 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)

34. 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)

35. 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
(Cruz-Flores 2011, Image
for urgent treatment from truthbeautynow.com)

36. Our Positions (tPA for AIS)
1. increase public education
○ risk factors & warning signs
○ time-sensitive treatment window
2. support allowing tPA administration for AIS
up to 4.5 hours after onset of symptoms if
eligibility criteria met

37. Questions?

38. References
AHA 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

39. References
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

40. References
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

41. References
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

42. 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