Intravenous Thrombolytic Therapy for Acute Ischemic Stroke

Bruchanski NataliaAlameda County Medical CenterHighland General HospitalAugust 2011

Bruchanski NataliaAlameda County Medical CenterHighland General HospitalAugust 2011

Lawrence R. Wechsler, MD. N Engl J Med 364;22

Statistics

• 795,000 new strokes each year, in US

• More than 150 000 deaths each year, 436 each day.

• 1 stroke every 53 seconds, 1 death from stroke every 3.3 minutes!

• More than 25% of stroke survivors older than age 65 years are disabled 6 months later

• 795,000 new strokes each year, in US

• More than 150 000 deaths each year, 436 each day.

• 1 stroke every 53 seconds, 1 death from stroke every 3.3 minutes!

• More than 25% of stroke survivors older than age 65 years are disabled 6 months later

Acute Medical Treatment of Stroke

Restore Blood Flow– Thrombolytics– Mechanical devices

Stroke progression or recurrent thromboembolism

– Anticoagulants– Antiplatelet agents

Restore Blood Flow– Thrombolytics– Mechanical devices

Stroke progression or recurrent thromboembolism

– Anticoagulants– Antiplatelet agents

Recombinant Tissue Plasminogen Activator (rtPA)

Tissue Plasminogen Activator for Acute Ischemic StrokeThe National Institute of Neurological Disorders and Stoke rt-PA Stroke Study Group

N Engl J Med 333; 24. Dec 1995

• Approved by The US Food and Drug Administration (FDA) in 1996• National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke

Study: •RCT. 624 patients •Given 0.9 mg/kg IV, maximum 90 mg within 3 hours of symptoms onset Results: •Favorable outcomes* achieved as compared with placebo at 90 days, 6 months and 1 year. Relative increase in recovery of 32% in tPA vs. 20% in placebo. P<0.05 •Symptomatic brain hemorrhage within 36 hs after onset of stroke, occurred in 6.4% in rtPA vs. 0.6% in placebo (p<0.001) Patients with symptomatic

intracranial hemorrhage had more severe deficits at base line (median NIHSS score, 20) than the study population (median NIHSS score, 14)

•Mortality rate in the 2 treatment groups similar at 3 months 17% in tPA group vs. 21% in placebo p=0.30

*Outcomes measured: Barthel Index, Mod Rankin Scale, GSW, NIHSS

• Approved by The US Food and Drug Administration (FDA) in 1996• National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke

Study: •RCT. 624 patients •Given 0.9 mg/kg IV, maximum 90 mg within 3 hours of symptoms onset Results: •Favorable outcomes* achieved as compared with placebo at 90 days, 6 months and 1 year. Relative increase in recovery of 32% in tPA vs. 20% in placebo. P<0.05 •Symptomatic brain hemorrhage within 36 hs after onset of stroke, occurred in 6.4% in rtPA vs. 0.6% in placebo (p<0.001) Patients with symptomatic

intracranial hemorrhage had more severe deficits at base line (median NIHSS score, 20) than the study population (median NIHSS score, 14)

•Mortality rate in the 2 treatment groups similar at 3 months 17% in tPA group vs. 21% in placebo p=0.30

*Outcomes measured: Barthel Index, Mod Rankin Scale, GSW, NIHSS

0

10

20

30

0

10

20

30

tPA tPAPlacebo Placebo

32

20 17

6.4

21

0.1

Excellent Recovery (%) Total Death Total Death Rate (%)Rate (%)

Hemorrhage

NINDS rt-PA Stroke Trial N Engl J Med 333; 24. Dec 1995

IV tPA for Acute Ischemic Stroke, Negative studies

ECASS I ECASS II ATLANTIS

Study/ Year RCT/1995 RCT/1998 RCT/1999

N 620 800 613

rtPA dose 1.1 mg/Kg 0.9 mg/Kg 0.9 mg/Kg

Treatment Window

0-6 hs 0-6 hs 3-5 hs

Primary Outcome

BI, RS at 90 days BI, RS at 90 days NIHHS, BI, RS and GSW at 30 and 90 days

Results No difference in Primary end point with increase mortality and risk of ICH in rtPA group

Similar to ECASS I without increase in mortality in control group

No differences in primary end point between groups. Increase in ICH rate and mortality

Inconvenients Less strict BP control, higher dose, and window

80% were treated at 4-5 hAverage time to Tx 4.5 hs

Observations Subgroup treated within 3 hs had benefit with rtPA

RCT of IV tPA for Acute Ischemic Stroke

Study N Dose Time window

ECASS I 650 1.1 0-6

NINDS 624 0.9 0-3

ECASS II 800 0.9 0-6

ATLANTIS A 142 0.9 0-6

ATLANTIS B 619 0.9 3-5

Association of outcome with early stroke treatment: Pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.

Lancet. 2004; 363(9411):768-74

Time (mins) Odds Ratio for favorable outcomes

95% CI Interval

0-90 2.8 1.8-4.5

91-180 1.5 1.1-2.1

181-270 1.4 1.1-1.9

271-360 1.2 0.9-1.5

Association of outcome with early stroke treatment: Pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.

Lancet. 2004; 363(9411):768-74

ECASS III• RCT. 821 patients. 2008 • Intravenous rtPA 0.9 mg/kg IV vs. Placebo• 3-4.5 hours after onset of symptoms (Average time 3h, 59 min)• Additional Exclusion Criteria: More than 80 years old Severe Stroke (NIHSS >25 or hypodensity > 1/3 of MCA on CT)

Prior treatment with anticoagulants History of both stroke and Diabetes

• Results: - Favorable outcome: 52.4 % in rtPA vs.45.2% in placebo Odds ratio 1.34, 95% CI, 1.02-1.76; p=0.04 - Symptomatic ICH rate: 2.4 % in rtPA vs. 0.2 % in placebo group. P=0.008 - Mortality: 7.7 % in rtPA vs. 8.4 % in placebo

• RCT. 821 patients. 2008 • Intravenous rtPA 0.9 mg/kg IV vs. Placebo• 3-4.5 hours after onset of symptoms (Average time 3h, 59 min)• Additional Exclusion Criteria: More than 80 years old Severe Stroke (NIHSS >25 or hypodensity > 1/3 of MCA on CT)

Prior treatment with anticoagulants History of both stroke and Diabetes

• Results: - Favorable outcome: 52.4 % in rtPA vs.45.2% in placebo Odds ratio 1.34, 95% CI, 1.02-1.76; p=0.04 - Symptomatic ICH rate: 2.4 % in rtPA vs. 0.2 % in placebo group. P=0.008 - Mortality: 7.7 % in rtPA vs. 8.4 % in placebo

American Heart Association Recommendations Stroke, 2007, 2009

• 2007Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for selected patients who may be treated within 3 hours of onset of ischemic stroke (Class I, Level of Evidence A)

• 2009,Addendum: Intravenous rtPA should be given to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke (Class I, level of evidence B). This window frame adds 4 new exclusion citeria.

• 2007Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for selected patients who may be treated within 3 hours of onset of ischemic stroke (Class I, Level of Evidence A)

• 2009,Addendum: Intravenous rtPA should be given to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke (Class I, level of evidence B). This window frame adds 4 new exclusion citeria.

Inclusion Criteria

•Diagnosis of Ischemic Stroke causing measurable neurologic deficit

•Onset of symptoms < 3 hours before start of treatment or in selected cases < 4.5 hours

•Age > 18

•Diagnosis of Ischemic Stroke causing measurable neurologic deficit

•Onset of symptoms < 3 hours before start of treatment or in selected cases < 4.5 hours

•Age > 18

Exclusion Criteria

Exclusion Criteria

Discussion Question

How would you evaluate, and explain to a patient, the risk/benefit balance of using rt-PA?

To what extent do you think the claims of this review can be applied to our work at Highland?

Number Needed to Treat or Harm:

_________1_________Absolute Increase in Benefit or Risk

Conclusions

Likelihood of Being Harmed or Helped:

____Absolute Benefit Increase__Absolute Risk Increase

=____12% better outcome____

6% symptomatic ICH

Conclusions

For patients who would have been included in the NINDS study, therapy with rt-PA is twice as likely to help their neurological deficit as it is to cause a symptomatic ICH.

Conclusions

Conclusion

The available evidence suggests rt-PA has a significant potential to improve neurologic outcomes in people who meet the inclusion criteria of the NINDS trial and no accepted exclusion criteria.

Significant practical barriers exist to acting on this data in many settings.