accomplishments in stroke care

Accomplishments in Stroke Care

Patrick D. Lyden, MD

UCSD Stroke Center

VAMC San Diego

NINDS Symposium, 2002

NIH Guidelines for Stroke Teams

www.stroke-site.orgProceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke December 12-13, 1996

• 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

http://www.stroke-site.org/


Before Thrombolysis

• Thornton Emergency

• 120 Minutes after Stroke Start


After Thrombolysis

• Clinic Visit

• 11 days after stroke


Pivotal Trials

Year Series N (tPA) SICH Outcome

1995 ECASS 620 (313) 29.3% (35.7%)

1995 NINDSParts 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


Larger treatment effect = smaller sample size

Treatment Effect:12% 2.6%

N=600 N=5000Sample Size:

Post-Pivotal TrialsYear Series N SICH Outcome

1998 Cologne 100 5% 40%

1999 Oregon 33 9.1 36.4%

2000 Lyon 200 4% 45%

2000 STARS 389 3.3% 11.5%

2000 Vancouver 46 2.2% 43%

2001 Berlin 75 2.7% 40%

2001 Barber 84 7.1% 54%

2001 Houston 269 5.6% Impr NIHSS

2002 CASES 1099 4.6% 46%


Relationship between Protocol Violations and ICH

Study Time Rx BP Coag ICH PSTARS 41% 33% 25% 18% 3% NSCleveland 27% 74% 14% 16% ?Houston 10% 7% NSCalgary 9% 9% 9% <0.05

USA 8% 15% 3% 4% 6% NSIndianapolis 25% 13% 25% 10% <0.02


Current Use of thrombolysis

1.8% Medicare Stroke patients Range 2 to 3 % in many

community surveys 20 to 25% if Stroke Team


The Innovation EffectThe 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 176:198-199

– “We suggest randomly allocating patients into –our trial--. Details are available from the author’s web site”

Etc Etc


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 TPA Stroke Study: NINDS TPA Stroke Study: Time to Treatment and Odds Ratio of Favorable OutcomeTime to Treatment and Odds Ratio of Favorable Outcome

MinutesMinutesStroke Onset To Start of TreatmentStroke Onset To Start of Treatment

6060 7070 8080 9090 100100 110110 120120 130130 140140 150150 160160 170170 180180

Od

ds

Rat

io

Od

ds

Rat

io

Fav

ora

ble

Ou

tco

me

Fav

ora

ble

Ou

tco

me

00

11

22

33

44

55

66

77

88

Benefit for rt-PABenefit for rt-PA

No Benefit for rt-PANo Benefit for rt-PA


“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


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 alNeurology 2001;56:1015-20


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


Favorable 3-month Outcome in NINDS Stroke Trial

0.0 1.0 2.0 3.0 4.0 5.0

Odds Ratios (adjusted)

NIHSS at baseline >5,<=20 91-180min (n=210)

NIHSS at baseline <=20 91-180min (n=246)

NIHSS at baseline >5, 91-180min (n=284)

All 91-180min (n=320)

All 0-90min (n=302)

All (n=622)

All* (n=624)

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


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 2002 176;198-199


CT Findings Do Not Exclude

Patel, et alJAMA 2001

NINDS Symposium, 2002Stroke 2002;33:2236-2242

Cerebral Hemorrhage in the Australian Streptokinase Trial

OR (CI) for PH1 and 2

0 0.1 1.0 10 100

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


Ethos Stroke Registry

15,500 Patient Records in Internet Registry Over 100 hospitals Represents Hospitals focusing on Acute

Stroke Treatment Average Age: 74 Male: 72 Female: 76 Gender of Pts: Male: 44% Female: 56% Ethnicity: White 83%Black 12% Hispanic 1%

Asian 0.6% Other 0.8% Unk 2&


Ethos—tPA Treated

Ischemic Stroke Pts rec’d IV-tpa 6.3%

Systemic Hemorrhage <48hrs/TX 6.6%


Ethos—Reasons for Non-treatment with tPA

Time 39.2% CT findings 13.1 Rapid Improvement 13.0 Stroke Severity 5.3 Age 3.7 Uncontrolled Hypertension 2.1 Unknown 8.8


Ethos—Onset to ED Arrival 0-1 hour 12.9% 1-2 hours 9.9 2-3 hours 5.7 3-4 hours 3.5 4-5 hours 2.5 5-6 hours 1.6 > 6 hours 24.2 Unknown/ND 39.6


Ethos—Time to Treatment

NINDS 0-3 hr arrival 3-6 hrOnset to ED N/A 69 2501st Seen by MD 10 10 18Image Initiated 25 44 63Results Rcvd 45 72 96TX Given 60 91 N/A

(times are in minutes and are Median times)


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


0,1 2,3 4 Death

ED Physicians can safely use tPA for acute stroke(3-month Rankin scores)

% Patients with mRankin Scale 0 to 5

NINDS

ER Docs

Neuro

Akins et alNeurology 2000;55:1801-05


Volume improves outcome:Trauma Experience


Some General Management Issues

Oxygen Hyperthermia Glucose Blood Pressure Heparin


www.humanapress.com


Shall We Implement What We Have?

It seems reasonable to proceed with what we have recognizing:

1. The need for innovationinnovation 2. The need for furtherfurther 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.


11

5

0

0

22

9

26

14

19

41

26

41

48

45

48

45Placebo

T-PA

Placebo

T-PA

NIHSS

Barthel

0-1 2-8 > 8 Death

100-95 90-55 50-0 Death

Effect of tPA in the Oldest, Most Severe Patients (49 patients found on admission to have age>75 and NIHSS > 20)

Generalized Efficacy of t-PA for Acute Stroke: Subgroup Analysis of the NINDS t-PA Stroke Trial. Stroke 28(11):2119-2124, 1997


20

8

22

18

17

20

19

19

10

11

14

10

11

15

15

18

13

21

16

20

23

16

10

10

0 1 2 3 4 Death

Placebo

T-PA

Placebo

T-PA

ECASS 2

ECASS 1

% Patients with mRankin Scale 0 to 5


STARS: Phase 4 Experience

N= 389Time to treat 2h 45m30 day Mortality 13%Favorable Outcome 35%Hemorrhage in 3.3%JAMA 2000, 283:1145-1150, Albers et al


Questions


Intracerebral Hemorrhage Rates After IV t-PA

Series, y

Patients, No.

Patients With

ICH, %

Patients With Symptomatic

ICH, % NINDS trials, 1995

312

11

6

STARS, 1999

296

10

3

Muticenter Survey, 1999

189

9

6

Cologne, 1998

100

11

5

Minnesota, 1998

97

13

9

Cleveland, 2000

70

22

16

Michigan, 1999

54

15

9

Indianapolis, 1999

41

22

12

Houston, 1998

30

10

7


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%


Further Experience in Houston


Risk of ICH by Deviation from NINDS Protocol

8.3

3.8

10.7 10.7

0

2

4

6

8

10

12

All ICH SymptomaticICH

% IC

H

Within Protocol

ProtocolDeviations

p=0.59 p=0.06


Atlantis Study

• Treatment with 0.9 mg/kg over one hour (Total N = 613)

• Target population (N=547) - patients treated within 3-5 hours


Atlantis Study - Results

Day 90 Placebo (n=275)

t-PA (n=272)

P value

NIHSS 0 or 1 32 34 .65 Rankin 0 or 1 39 42 .42 NIHSS >11 36 45 .03


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 alStroke 2000;31:2920-24


Cleveland Area Study

5000 strokes in one year– 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%


Placebo

Ancrod

STAT Study

% Patients with Barthel Index Scores


TNK: A New Clot-Buster


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.

www.stroke.org


Studies Prior to Pivotal

Year Series N (tPA) SICH Outcome

1992 NIH 0-90 (74) 4% (46%)*

1992 Haley 0-180 (20) 10% (15%)

1992 Mori 6h 31 (19) 8% (11%)

Incr scores HSS

1993 Bridging 27 (14) 0% 15% (47%)

* NIHSS >=4 points at 24 hours


NIH Guidelines for Stroke Teams

www.stroke-site.orgProceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke December 12-13, 1996

• 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

accomplishments in stroke care

Documents

stroke teamswww

stroke carepatrick

treatment of acute stroke

patients nihss

ethos stroke registry15

medicare stroke patientsrange

poorlyof patients

eicmild patients