2. Accomplishments in Stroke Care
Patrick D. Lyden, MD
UCSD Stroke Center
VAMC San Diego

3. NIH Guidelines for Stroke Teams
• Door to doctor: 10 min
• Door to CT scan: 25 min
• Door to CT reading: 45 min
• Door to drug: 60 minutes
• Door to monitored bed: 3 hours
Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke December 12-13, 1996
NINDS Symposium, 2002

4. Before Thrombolysis Thornton Emergency 120 Minutes after Stroke Start
NINDS Symposium, 2002

5. After Thrombolysis Clinic Visit 11 days after stroke
NINDS Symposium, 2002

6. Pivotal Trials Year Series N (tPA) SICH Outcome 1995 ECASS 620 (313)
29.3% (35.7%)
NINDS
Parts 1+2
624 (312)
0.6% (6.4%)
26% (39%)
1997
ECASS II
800 (409)
3.4% (8.8%)
36.6% (40.3%)
2000
STAT
500 (248)
2% (5%)
34.4% (42.2%)
1988
Asset
4975 (2516)
0.4% (1.4%)
(7.2%) 9.8% mortality
NINDS Symposium, 2002

7. Larger treatment effect = smaller sample size
12%
Treatment Effect:
2.6%
N=600
Sample Size:
N=5000
NINDS Symposium, 2002

8. Post-Pivotal Trials Year Series N SICH Outcome 1998 Cologne 100 5% 40%
1999
Oregon 33
9.1
36.4%
2000
Lyon
200 4%
45%
STARS
389
3.3%
11.5%
Vancouver 46
2.2%
43%
2001
Berlin 75
2.7%
Barber 84
7.1%
54%
Houston
269
5.6%
Impr NIHSS
2002
CASES
1099
4.6%
46%

9. Relationship between Protocol Violations and ICH
Study
Time Rx BP
Coag
ICH P
STARS
41%
33%
25%
18% 3% NS
Cleveland
27%
74%
14%
16% ?
Houston
10% 7%
Calgary 9%
<0.05
USA 8%
15% 4% 6%
Indianapolis
13%
<0.02
NINDS Symposium, 2002

10. Current Use of thrombolysis
1.8% Medicare Stroke patients
Range 2 to 3 % in many community surveys
20 to 25% if Stroke Team
NINDS Symposium, 2002

11. The Innovation Effect: To Justify Innovation, first Indict the Status Quo
No vascular imaging in ECASS or NINDS
Need better thrombolytics
NINDS, “only 1 of which was +”
2002, West J Med 176:
“We suggest randomly allocating patients into –our trial--. Details are available from the author’s web site”
Etc Etc
NINDS Symposium, 2002

12. The Innovation Effect Reduces Treatment
Non-specialists are confused
Does thrombolysis work or not?
Do I need an angiogram or not?
Do I need a PET or MRI scan or not?
Our bona fide disagreements may be magnified for nefarious purposes.
Payers who don’t want to pay
Regulators who don’t want to approve
NINDS Symposium, 2002

13. Stroke Onset To Start of Treatment
NINDS TPA Stroke Study:
Time to Treatment and Odds Ratio of Favorable Outcome 8 7 6 5
Favorable Outcome
Odds Ratio 4 3 2
Benefit for rt-PA 1
No Benefit for rt-PA m 60 70 80 90
100
110
120
130
140
150
160
170
180
Minutes
Stroke Onset To Start of Treatment

14. “Only a few stroke patients are eligible”
27% of all stroke patients present within 3 hours.
Of these, many are excluded for “too mild”, rapidly improving, or CT showing EIC
NINDS Symposium, 2002

15. Mild Patients do Poorly
Of patients excluded from treatment for mild or rapidly improving symptoms, 32% were dead or dependent at discharge.
Of 15 patients excluded for CT abnormalities, only 4 (27%) were confirmed on retrospective review as valid exclusions
Barber et al
Neurology 2001;56:
NINDS Symposium, 2002

16. Did Mild Patients Unbalance the Trial?
Patients NIHSS 0 to 5 were enrolled:
42 in tPA, 16 in placebo
First NEJM paper was adjusted for this using Multi-variable methods
All subsequent papers likewise adjusted
NINDS Symposium, 2002

17. Favorable 3-month Outcome in NINDS Stroke Trial
Odds ratios are adjusted for Age, baseline NIHSS, admission MBP, Diabetes, Early CT findings (Edema, hypodensity or intravascular thrombus), age x NIHSS, age admission MBP and center
*Included two patients who were randomized after 180 minutes from stroke onset
NINDS Symposium, 2002

18. Is there a significant Effect?
Independent analysis (without data) suggests the imbalance produces 4% of the observed 12% treatment effect (ie 1/3)
Wardlaw, Lindley, Lewis. West J. Med May ;
NINDS Symposium, 2002

19. NINDS Symposium, 2002

20. CT Findings Do Not Exclude
NINDS Symposium, 2002
Patel, et al
JAMA 2001

21. Cerebral Hemorrhage in the Australian Streptokinase Trial
OR (CI) for PH1 and 2
No EIC (n=46 plac, 38 SK)
EIC <1/3 (n=45 plac, 37 SK)
EIC >1/3 (n=45 plac, 49 SK)
SK* (n=34 heme, 236 no heme)
sBP* ‘’
* After multivariate adjustment
NINDS Symposium, 2002
Stroke 2002;33:

22. NINDS Symposium, 2002

23. Ethos Stroke Registry 15,500 Patient Records in Internet Registry
Over 100 hospitals
Represents Hospitals focusing on Acute Stroke Treatment
Average Age: Male: Female: 76
Gender of Pts: Male: 44% Female: 56%
Ethnicity: White 83%Black 12% Hispanic 1% Asian 0.6% Other 0.8% Unk 2&
NINDS Symposium, 2002

24. Ethos—tPA Treated Ischemic Stroke Pts rec’d IV-tpa 6.3%
Systemic Hemorrhage <48hrs/TX 6.6%
NINDS Symposium, 2002

25. Ethos—Reasons for Non-treatment with tPA
Time %
CT findings
Rapid Improvement
Stroke Severity
Age
Uncontrolled Hypertension 2.1
Unknown
NINDS Symposium, 2002

26. Ethos—Onset to ED Arrival
0-1 hour %
1-2 hours
2-3 hours
3-4 hours
4-5 hours
5-6 hours
> 6 hours
Unknown/ND
NINDS Symposium, 2002

27. Ethos—Time to Treatment
NINDS 0-3 hr arrival hr
Onset to ED N/A
1st Seen by MD
Image Initiated
Results Rcvd
TX Given N/A
(times are in minutes and are Median times)
NINDS Symposium, 2002

28. Summary
tPA within 3 hours is effective and safe, but underutilized, partly due to the innovation effect
Improvement must follow wider application of routine 3-hour use of IV tPA for acute stroke
NINDS Symposium, 2002

29. ED Physicians can safely use tPA for acute stroke
(3-month Rankin scores)
NINDS
ER Docs
Neuro
% Patients with mRankin Scale 0 to 5
Akins et al
Neurology 2000;55:
NINDS Symposium, 2002

30. Volume improves outcome: Trauma Experience
NINDS Symposium, 2002

31. Some General Management Issues
Oxygen
Hyperthermia
Glucose
Blood Pressure
Heparin
NINDS Symposium, 2002

32.
NINDS Symposium, 2002

33. Shall We Implement What We Have?
It seems reasonable to proceed with what we have recognizing:
1. The need for innovation
2. The need for further studies: especially IST-3, ECASS-3, SITS-MOST, DIAS, etc.
3. A target of 12% of all strokes has been shown to be feasible with current methods.
NINDS Symposium, 2002

34. Effect of tPA in the Oldest, Most Severe Patients
(49 patients found on admission to have age>75 and NIHSS > 20)
Placebo
T-PA
NIHSS
Barthel
> Death
Death
Generalized Efficacy of t-PA for Acute Stroke: Subgroup Analysis of the NINDS t-PA Stroke Trial. Stroke 28(11): , 1997

35. % Patients with mRankin Scale 0 to 5
tPA >1/3
ECASS 1
% Patients with mRankin Scale 0 to 5
tPA <1/3
Placebo >1/3
tPA
Placebo
NINDS Symposium, 2002

36. % Patients with mRankin Scale 0 to 5
Placebo
T-PA
ECASS 2
ECASS 1
% Patients with mRankin Scale 0 to 5
These bars illustrate the NIHSS and Barthel Index results for 49 patients greater than age 75 and presenting with NIHSS greater than 22 before treatment.
NINDS Symposium, 2002

37. STARS: Phase 4 Experience
Time to treat 2h 45m
30 day Mortality 13%
Favorable Outcome 35%
Hemorrhage in 3.3%
JAMA 2000, 283: , Albers et al
NINDS Symposium, 2002

38. Questions
NINDS Symposium, 2002

39. Intracerebral Hemorrhage Rates After IV t-PA
NINDS Symposium, 2002

40. Community Experience Houston 3 hospitals (1 University)
One year after t-PA results published
Followed protocol
Treated 30/267 stroke codes with t-PA
Favorable Outcome in 37%
Symptomatic Hemorrhage in 7%
NINDS Symposium, 2002

41. Further Experience in Houston
NINDS Symposium, 2002

42. Risk of ICH by Deviation from NINDS Protocol
p= p=0.06
NINDS Symposium, 2002

43. Atlantis Study Treatment with 0.9 mg/kg over one hour (Total N = 613)
Target population (N=547) - patients treated within 3-5 hours
NINDS Symposium, 2002

44. Atlantis Study - Results

45. Vancouver Hospital Stroke Team QA survey
1996 to 1999 saw n=29 plus transfers n=17 (1.8% of all strokes)
Hemorrhage rate 2.2%
Response rate 43% (Rankin)
Chapman et al
Stroke 2000;31:
NINDS Symposium, 2002

46. Cleveland Area Study 5000 strokes in one year 17% within 3 hours
4345 Ischemic
17% within 3 hours
70 (1.8%) got tPA
Range 0 to 10.2%
Protocol Deviations in 50%
Anti-coagulants 37%
Hypertension 7%
NINDS Symposium, 2002

47. STAT Study Placebo Ancrod % Patients with Barthel Index Scores
These bars illustrate the NIHSS and Barthel Index results for 49 patients greater than age 75 and presenting with NIHSS greater than 22 before treatment.
% Patients with Barthel Index Scores
NINDS Symposium, 2002

48. TNK: A New Clot-Buster
NINDS Symposium, 2002

49. NSA Guidelines for Stroke Centers
1. The Center has an established EMS protocol for the emergency treatment and delivery of stroke patients.
2.      All members of the stroke team comply with the availability and response requirements of a 24 hour Stroke Center.
3.      The Center has a written stroke team activation protocol that establishes the criteria for notification of the stroke team and identification of acuity or degree of symptoms of stroke. The protocol should also identify the stroke team members who are to be notified when a stroke patient is enroute or has arrived at the facility.
NINDS Symposium, 2002

50. Studies Prior to Pivotal
Year
Series
N (tPA)
SICH
Outcome
1992
NIH 0-90
(74) 4%
(46%)*
Haley 0-180
(20)
10%
(15%)
Mori 6h
31 (19)
8% (11%)
Incr scores HSS
1993
Bridging
27 (14) 0%
15% (47%)
* NIHSS >=4 points at 24 hours
NINDS Symposium, 2002

51. NIH Guidelines for Stroke Teams
• Door to doctor: 10 min
• Door to CT scan: 25 min
• Door to CT reading: 45 min
• Door to drug: 60 minutes
• Door to monitored bed: 3 hours
Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke December 12-13, 1996
NINDS Symposium, 2002

52. A Patient
NINDS Symposium, 2002

53. Early Improvement NINDS Symposium, 2002
Annals of Emergency Medicine 30 (5): , 1997.
NINDS Symposium, 2002

54. Before We Innovate, Shall We Implement What Works?
Patients who arrive within 2 hours
Patients who fit NINDS criteria
Patients without acute hypodensity on CT
NINDS Symposium, 2002

55. The imbalance at baseline does not explain the overall study effect:
Rankin (0,1) at 3 months
0-90 min RR 1.4 (1.0,2.0)
RR 1.8 (1.3,2.5
Without NIHSS 0-5 Patients
(1.0, 2.1)
(1.1, 2.4)
(about 25%)
NINDS Symposium, 2002