Transcript Maximizing IV Thrombolytic Therapy in Acute Ischemic Stroke Kamakshi Lakshminarayan, MD PhD Assistant Professor Neurology & Epidemiology University of Minnesota Great Lakes Regional Stroke Network October 8,

Maximizing IV Thrombolytic
Therapy in Acute Ischemic Stroke
Kamakshi Lakshminarayan, MD PhD
Assistant 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 Stroke
3050
Time and date last well known documented
YES
1431 (47%)
NO
1619 (53%)
Came within 2 hours of symptom onset
YES
417 (29%)
NO
1014 (71%)
7/1619
received IV tPA
Received IV tPA
Numerator:
YES
112 (27%)*
NO
305 (73%)
10/1014
received IV tPA
Documented contraindications
YES
177 (58%)
NO
128 (42%)*
*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
0-1.5 h
Odds Ratio for
normal at 3 mo.
2.81
Hemorrhage
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
<3 h
3-4.5 h
% normal at
3 mo.
40%
ICH
7.3%
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 Symptomatic
mo.
ICH
52%
7.9%
tPA*
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!