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

Presentation will deal with a currently off label use of tPA

Agenda

Maximizing Opportunities for tPA delivery

• Expanded time window for treatment

• Management of rapidly improving or mild strokes

• IV thrombolysis in the elderly

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

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 (*).

When are patients arriving?

Time Hours N Percent

0-2 315 13

> 2-3.5 162 7

> 3.5-6 211 9

> 6 391 16

Missing 1306 55

Minnesota Stroke Registry: 2008

An Expanded Time Window Will Help

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

within 2 hours of symptom onset

Widening the time window for IV tPA treatment to 4.5h: 3 reports

1. Pooled analysis of early 0-6 h IV tPA placebo controlled trials – Lancet 2004

2. Registry comparing cohorts treated with IV tPA < 3 vs. 3-4.5 h – Lancet 2008

3. RCT of tPA vs. placebo in 3-4.5 h – ECASS-3 NEJM 2008

IV tPA: Pooled analysis of outcome vs. onset to treatment (OTT) time

Six randomized controlled IV tPA trials

2775 patients

0-6 h OTT

0.9 mg/kg (except ECASS I - 1.1 mg/kg)

Median NIHSS = 11 (moderate deficit)

The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators, Lancet 2004

Continued . . .

OTT

Odds Ratio for normal at 3 mo.

Hemorrhage

0-1.5 h 2.81 3.1%

1.5-3 h 1.55 5.6%

3-4.5 h 1.40 5.9%

4.5-6 h 1.15 6.9%

The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators, Lancet 2004

IV tPA: observational study of outcome & OTT <3 vs. 3-4.5 h

European Union phase IV study

Compared outcome: OTT 3-4.5 h – 664 patients OTT <3 h – 11,865 patients

All received 0.9 mg/kg tPA

3-4.5 h patients slightly younger (65 vs. 68) and had lower median NIHSS (11 vs. 12)

Safe Implementation of Treatments in Stroke (SITS) Investigators, Lancet 2008

Continued . . .

OTT

% normal at 3 mo.

ICH

<3 h 40% 7.3%

3-4.5 h 41% 8.0%

Safe Implementation of Treatments in Stroke (SITS) Investigators, Lancet 2008

ECASS-3 Trial

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

– Placebo n=403

• Treat within 3-4.5 hours of symptom onset

• Median time to treatment 4 hours

• tPA 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 within 24 hours

Summary of ECASS-3

% Normal at 3 mo.

Symptomatic ICH

tPA* 52% 7.9%

Placebo** 45% 3.5%

Hacke, N Engl J Med 2008

*OR 1.34 (1.02-1.74) P = 0.04

**p = 0.006

AHA Guideline Recommendations

IV tPA 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 tPA 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 tPA

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 RIMS

Case series:– 876 IS patients with 24 hours– 162 (19%) did not receive IV tPA due to RIMS Nedeltchev et

al. Stroke 2007

Calgary study:– 314 IS patients came within 3 hours– 98 (31%) did not receive IV tPA due to RIMS Barber et al.

Neurology 2001

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

Discharge Outcomes

Minnesota Stroke Registry:

• 76 patients no tPA due to RIMS

• Prior to this stroke 69 (91%) ambulated independently

• At d/c 38 (50%) ambulated independently!

And…..

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

And…..

Calgary Study:

• 98 patients did not receive IV tPA 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 tPA?

Treated with IV tPA

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

• Cochrane meta-analysis: 42 patients > 80 years in thrombolysis RCT – NINDS trial included a few patients over 80 years– ECASS-3 did not– IST-3 does and is still recruiting till 2011

• 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

Summary

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

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 patient and family and treat

Questions?

Thank you!