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

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 www.stroke-site.org Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke December 12-13, 1996 NINDS Symposium, 2002

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

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

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

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

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%

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

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

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 176:198-199 “We suggest randomly allocating patients into –our trial--. Details are available from the author’s web site” Etc Etc NINDS Symposium, 2002

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

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

“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

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;56:1015-20 NINDS Symposium, 2002

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

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

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 NINDS Symposium, 2002

NINDS Symposium, 2002

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

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

NINDS Symposium, 2002

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& NINDS Symposium, 2002

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

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 NINDS Symposium, 2002

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 NINDS Symposium, 2002

Ethos—Time to Treatment NINDS 0-3 hr arrival 3-6 hr Onset to ED N/A 69 250 1st Seen by MD 10 10 18 Image Initiated 25 44 63 Results Rcvd 45 72 96 TX Given 60 91 N/A (times are in minutes and are Median times) NINDS Symposium, 2002

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

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;55:1801-05 NINDS Symposium, 2002

Volume improves outcome: Trauma Experience NINDS Symposium, 2002

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

www.humanapress.com NINDS Symposium, 2002

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

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 0-1 2-8 > 8 Death 100-95 90-55 50-0 Death Generalized Efficacy of t-PA for Acute Stroke: Subgroup Analysis of the NINDS t-PA Stroke Trial. Stroke 28(11):2119-2124, 1997

% 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

% 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

STARS: Phase 4 Experience Time to treat 2h 45m 30 day Mortality 13% Favorable Outcome 35% Hemorrhage in 3.3% JAMA 2000, 283:1145-1150, Albers et al NINDS Symposium, 2002

Questions NINDS Symposium, 2002

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

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

Further Experience in Houston NINDS Symposium, 2002

Risk of ICH by Deviation from NINDS Protocol p=0.59 p=0.06 NINDS Symposium, 2002

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

Atlantis Study - Results

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;31:2920-24 NINDS Symposium, 2002

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

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

TNK: A New Clot-Buster NINDS Symposium, 2002

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 NINDS Symposium, 2002

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

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 www.stroke-site.org Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke December 12-13, 1996 NINDS Symposium, 2002

A Patient NINDS Symposium, 2002

Early Improvement NINDS Symposium, 2002 Annals of Emergency Medicine 30 (5):676-682, 1997. NINDS Symposium, 2002

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

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) 91-180 RR 1.8 (1.3,2.5 Without NIHSS 0-5 Patients 0-90 1.5 (1.0, 2.1) 90-180 1.6 (1.1, 2.4) (about 25%) NINDS Symposium, 2002