Maximizing IV Thrombolytic Therapy in Acute Ischemic Stroke

Kamakshi Lakshminarayan, MD PhDAssistant Professor

Neurology & Epidemiology University of Minnesota

Great Lakes Regional Stroke Network October 8, 2009

Disclosures

K Lakshminarayan receives research grant support from the NIH and CDC

No off-label or investigational drugs/devices will be discussed

Classes of Recommendations• Class I: Evidence for and/or general agreement that the

treatment is useful and effective 

   • Class II: Conflicting evidence and/or a divergence of

opinion about usefulness/efficacy of a treatment        – IIa: Weight of evidence or opinion is in favor of the

treatment.       

–  IIb: Usefulness is less well established by evidence or opinion.   

•  Class III: Evidence and/or general agreement that the treatment is not useful and in some cases may be harmful

Levels of Evidence

• Level A : Data derived from multiple RCT  

• Level B: Data derived from single RCT or nonrandomized studies    

• Level C: Consensus opinion of experts

Maximizing Opportunities for rtPA delivery

• Expanded time window for treatment

• Management of rapidly improving or mild strokes

• IV thrombolysis in the elderly

An Expanded Time Window is Needed

Intravenous Thrombolytic Therapy: The Minnesota Stroke Registry Quarter 2, 2008 to Quarter 2, 2009

Ischemic Stroke3050

YES1431 (47%)

NO1619 (53%)

7/1619 received IV tPA

YES417 (29%)

NO1014 (71%)

10/1014 received IV tPA

Numerator:YES

112 (27%)*

NO 305 (73%)

YES177 (58%)

NO128 (42%)*

Time and date last well known documented

Came within 2 hours of symptom onset

Received IV tPA

Documented contraindications

*The thrombolytic therapy performance measure calculation is the numerator, indicated by the box labeled Numerator, divided by the denominator, the sum of the boxes indicated by the (*).

An Expanded Time Window is Needed!

Minnesota Stroke Registry: Less than 1/3 of patients with documented times come

within 2 hours of symptom onset

ECASS-3 Trial

• Multi-center prospective randomized controlled trial– rtPA n=418

– Placebo n=403

• Treat within 3-4.5 hours of symptom onset

• Median time to treatment 4 hours

• rtPA dosing regimen the same

Similarities to NINDS tPA Trial

Similar inclusion and exclusion criteria But additional exclusions:

– Age over 80 years

– NIHSS > 25

– Any oral anticoagulant use

– Previous stroke + DM

Ancillary Care Post Thrombolysis

Similar to NINDS trial except:

DVT prophylaxis with parenteral anticoagulants allowed

Outcomes of ECASS-3 & NINDS Trials - Disability

mRS of 0,1 at 3 months

ECASS-3: • 52% (rtPA) vs. 45% (control)

• OR 1.34 (1.02-1.74) P = 0.04

NINDS: • 39% (rtPA) vs. 26% (control)

• OR 1.7 (1.1-2.6) P = 0.019

Outcomes of ECASS-3 versus NINDS Trials - ICH

Symptomatic ICH (NINDS definition)

ECASS-3: • 7.9% vs. 3.5% (placebo) P = 0.006

NINDS:• 6.4% vs. 0.6% (placebo) P < 0.001

Outcomes of ECASS-3 versus NINDS Trials - Mortality

Death at 3 months

ECASS-3: • 32% vs. 34% (placebo) P = 0.68

NINDS: • 17% vs. 24% (placebo) P = 0.3

AHA Guideline Recommendations

IV rtPA is recommended for selected patients who may be treated within 3 hours of symptom onset of ischemic stroke

• Class I, Level A

AHA Guideline Recommendations

IV rtPA should be administered for those who can be treated 3-4.5 hours after symptom onset with similar exclusionary criteria as for within 3 hour window + age > 80, oral anticoagulant use, NIHSS > 25, history of stroke + DM

• Class I, Level B

In those with above additional exclusionary criteria – utility is not well established, needs further study

• Class IIb, Level C

Diffusion of Trial Evidence into Practice: Minnesota Stroke Registry

September 25, 2008: ECASS-3 published NEJM

May 28, 2009: AHA guideline recommendations on the expanded window online

Year Total IVT IVT w/in 3h IVT 3-4.5h IVT ? time

2008 86 76 (88%)* 6 (7%) 4 (5%)

2009 Q1 41 37 (90%) 4 (10%) 0

2009 Q2 48 42 (88%) 5 (10%) 1 (2%)

*% refers to all IV tPA cases as denominator

Rapidly Improving or Mild Strokes

Exclusions to IV rtPA

NINDS Trial:

• Patients excluded if rapidly improving or minor symptoms (RIMS)

AHA Guidelines:

• Neurological signs should not be clearing spontaneously

• Neurological signs should not be minor & isolated

How Often Does This Occur?

Minnesota Stroke Registry 2008 data: • 315 IS patients came within 2 hours • 76 (24%) did not receive IV tPA due to RIMSCase series:• 876 IS patients with 24 hours• 162 (19%) did not receive IV rtPA due to RIMS

(Nedeltchev et al. Stroke 2007)Calgary study:• 314 IS patients came within 3 hours• 98 (31%) did not receive IV rtPA due to RIMS Barber et

al. Neurology 2001

What happens to them when they are not treated with IV rtPA?

Discharge Outcomes

Minnesota Stroke Registry:• 76 patients no rtPA due to RIMS• Prior to this stroke 69 (91%) ambulated

independently• At d/c 38 (50%) ambulated independently!Case Series:• 41 patients not treated due to RIMS• 11/41 (27%) died or not discharged home due to

worsening (6) or persistent “mild deficit” (5) Smith et al. Stroke 2005

Discharge Outcomes

Calgary Study:

• 98 patients did not receive IV rtPA due to RIMS

• 32% of these remained dependent at discharge or died during hospitalization Barber et al. Neurology 2001

Outcomes at 3 Months

Case series 162 patients with RIMS:

• Favorable: 75% (122 patients, mRS 0,1)

• Unfavorable: 25% (40 patients, mRS > 1)– mRS 2 = 16%– mRS 3, 4 = 7%– Dead = 1%– 2 recurrent strokes

• No difference in outcomes between mild and rapidly improving Nedeltchev Stroke 2007

What if they are treated with IV rtPA?

Treated with IV rtPA

Case Series:

• 19 patients with rapid improvement were treated at mean NIHSS of 5 [range 1-6]

• 3 month outcomes: – one patient died due to recurrent stroke from AF– NIHSS at 3 months in remaining was 0, mRS range

0-1 Baumann et al. Stroke 2006

What should we do about them?

Management of Rapidly Improving or Minor Strokes

RIMS that have poor outcomes are a heterogeneous group

1. TIA – subsequently have strokes during hospitalization

2. Mild strokes – worsen during hospitalization

3. Seemingly mild strokes with low NIHSS but have gait ataxia or cognitive deficit not captured on the NIHSS Smith et al. Stroke 2005

Management

1. TIA• If clear resolution of symptoms restart the

clock if symptoms recur unless there are imaging correlates of tissue damage (DWI)

• Neuro-checks every 30-60 minutes for 1st 12 hours

2. Mild strokes – do not restart clock• Need clinical trials to guide treatment

decisions since this population were not included in the original trials

Elderly Patients

Limited data on thrombolysis in the elderly• NINDS trial included a few patients over 80

years• ECASS-3 did not• IST-3 does and is still recruiting till 2011• Cochrane meta-analysis: 42 patients > 80

years in thrombolysis RCT (not including IST-3)

• Anecdotal reports on nonagenarians and centenarians being treated

Thrombolysis in the Elderly

Main worry is the risk of ICH• Systematic review of 6 cohort studies

found similar likelihood of symptomatic ICH OR 1.22 (95% CI 0.77-1.94)

• Three times higher odds of dying after thrombolysis for those > 80

• Similar in those without thrombolysis – three times higher odds of dying

The Minnesota Experience

Minnesota Stroke Registry: Year 2008

• 33 patients 90 or older came within 2 hours of symptom onset

• 7 received IV rtPA, 2 died soon after

• 26 did not receive IV rtPA, 4 died soon after

Summary

1. ECASS-3 extends the thrombolysis time window beyond 3 hours with restrictions – class I Level A

2. Clinical trials are needed to evaluate thrombolysis in those with mild deficits or rapidly improving strokes

3. Paucity of data on elderly – await IST-3. Community practice is to discuss with family and treat

Questions?

Thank you!