The Golden Hour and Acute Brain Ischemia: Presenting Features and Lytic Therapy in Over 30,000 Patients Arriving within 60 Minutes of Onset at GWTG-S Hospitals Jeffrey L. Saver, MD; Eric E. Smith, MD, MPH; Gregg C. Fonarow, MD; Mathew J. Reeves, PhD; Xin Zhao, MS; DaiWai M. Olson, PhD, RN; Lee H. Schwamm, MD

Disclosures The Get With The Guidelines®–Stroke (GWTG-Stroke) program is provided by the American Heart Association/American Stroke Association. The GWTG-Stroke program is currently supported in part by a charitable contribution from Bristol-Myers Squib/Sanofi Pharmaceutical Partnership and the American Heart Association Pharmaceutical Roundtable. GWTG-Stroke has been funded in the past through support from Boehringer-Ingelheim and Merck. The individual author disclosures are listed in the manuscript

Background The benefit of intravenous thrombolytic therapy in acute brain ischemia is strongly time dependent Therapeutic yield is maximal in the first minutes after symptom onset and declines steadily during the first 3 hours

Background The Joint Commission target for Primary Stroke Centers is to achieve a Door-to-Needle time of within 60 minutes in 80% of patients Hospitals participating in the Get With The Guidelines®–Stroke Quality Improvement program have been shown to successfully deliver intravenous fibrinolytic therapy to patients arriving within the first 60 minutes of onset

Introduction The benefit of intravenous thrombolytic therapy in acute brain ischemia is strongly time dependent. Therapeutic yield is maximal in the first minutes after symptom onset and declines rapidly over the next 4.5 hours. In the typical large artery ischemic stroke, in each minute in which reperfusion is delayed, 2 million nerve cells die. Patients receiving treatment within the first 60 minutes (the “Golden Hour”) of onset of symptoms, have the greatest opportunity to benefit from recanalization therapy Hyperacute-arriving patients and their treatment have not previously not been well characterized

Objective To examine the frequency, characteristics and treatment of Ischemic Stroke patients arriving at hospitals within the “Golden Hour”

Methods Data Source Hospitals participating in GWTG-Stroke who utilize the web-based patient management tool for data collection Outcome Sciences, Inc. served as the data collection and coordination center The Duke Clinical Research Institute (DCRI) served as the data analysis center

Methods Study Population Between April 1, 2003 to December 31, 2007 905 GWTG-Stroke Hospitals 431,170 Ischemic Stroke and TIA patients arriving to Hospital Emergency Departments (ED’s) within 60 minutes of “last known well time”

Methods Case Identification Trained hospital personnel instructed to ascertain consecutive Acute Stoke Admissions Methods included regular surveillance of Emergency Dept. records, ward census logs and/or neurological consultations The eligibility of each acute stroke admission was confirmed at chart review prior to abstraction

Methods Characteristics Patient Data included: Demographics Medical history Initial head computerized tomography findings In-hospital treatment and events Discharge treatment Mortality Discharge destination

Methods Characteristics Hospital level data included: Bed size Academic or non-academic status Annual volume of stroke discharges Geographical region

Methods Data Analyzed Contingency tables were developed to assess differences in: Demographics (age, sex) Stroke severity Arrival Mode (ambulance, private vehicle) Door-to-Needle (DTN) Time Door-to-Imaging (DTI) Time Outcome Destination at Discharge Generalized estimating equations logistics regression models, accounting for in-hospital clustering, were generated to identify independent predictors of Onset-to-Door Time (OTD) and Door-to-Needle Time (DTN) < 60 minutes

Results Analysis Sample During the 4.75 year time period, at 905 hospital sites, data for 431,170 Ischemic Stroke and TIA patients were entered into the GWTG-Stroke database. Main analysis performed upon 106,924 patients in this cohort with Ischemic Stroke, a documented last known well-time and presentation directly to the Emergency Department by ambulance or private vehicle.

Results - Patient Characteristics ≤ 1 Hr 1-3 Hrs > 3 Hrs P value Age (SD) 71.5 (14.6) 72.1 (14.3) 70.6 (14.2) < 0.0001 Sex (Female) 50.8% 52.2% 51.5% 0.002 White, Non-Hispanic Black 77.3% 11.8% 77.5% 11.9% 72.5% 15.8% Arrival by ambulance 79.0% 72.2% 55.0.% NIHSS (median, IQR) 8 (3-16) 6 (2-12) 4 (2-9)

Patient and Hospital Level Characteristics Independently Associated with ED Arrival within the First 60 Minutes of Onset Characteristic OR (95% CI) P value Severe deficit (NIHSS 9-41 vs 0-3) 1.84 (1.76-1.93) <0.001 Arrival mode (EMS vs Private transportation 1.78 (1.70-1.87) H/o atrial fibrillation 1.21 (1.16-1.26) Moderate deficit (NIHSS 4-8 vs 0-3) 1.16 (1.10-1.22) CAD/prior MI 1.08 (1.03-1.12) Prior stroke/TIA 0.96 (0.92-1.00) 0.049 H/o HTN 0.95 (0.91-0.99) 0.018 Sex (F vs M) 0.94 (0.90-0.98) 0.002 Age (per 10 year increase) 0.91 (0.90-0.92) Race-ethnicity, Black vs White, non-Hispanic 0.91 (0.86-0.97 0.004 Hospital Region (South vs West) 0.87 (0.78-0.98) 0.024 Moderate annual hospital stroke admits (101-300 vs ≤100) 0.87 (0.78-0.97) 0.012 Smoker 0.84 (0.80-0.88) Race-ethnicity, Asian vs White, non-Hispanic 0.78 (0.68-0.89) Diabetes Mellitus 0.77 (0.74-0.80) High annual hospital stroke admits (>300 vs ≤100) 0.76 (0.66-0.87)

Result Patient Characteristics Patients with documented “Last Known Well Time”, saw a: Higher arrival by EMS Higher use of TPA Higher Stroke Severity Lower frequency of Blacks

Results Onset-to-Door Time 106,924 ischemic stroke patients arrived directly to GWTG-S hospital EDs by ambulance or private vehicle Onset to Door Times N Percent < 60 mins 30,220 28.3% 61-180 mins 33,858 31.7% > 180 mins 42,846 40.1% Among < 60 mins patients, mean onset to door (OTD) time: 39.9 mins (SD 14.8)

Results Time Of Arrival cohorts Race/Ethnicity Slightly more often were non-Hispanic white in both 1 hour or under and 1-3 hour arrival Less often Black or Asian in same time frames Stroke Severity Greatest among Golden Hour arriving patients Intermediate among 1-3 hour arriving patients Least among beyond 3 hour arriving patients Frequency of Arrival to Hospital by Ambulance 79% in 1 hour or under patients 72.2% in 1-3 hour patients 55% in beyond 3 hour patients All above groups similar in age and gender Arrival occurred mildly more often at hospitals located in the Northeast and West

Results Symptom Onset-to-Door Time Patient and Hospital Factors independently associated with Symptom OTD Time less than or equal to 1 hour (Golden Hour) Increased odds of early arrival Severe neurologic deficit Arrival by ambulance rather than private transport Atrial Fibrillation Decreased odds of early arrival Hospital location in the South Higher annual number of Stroke Admissions

Results IV TPA given to: 12,545 direct ED IS patients 159 direct ED aborted IS patients (TPA-induced TIA) 11.8% of all direct ED, IS patients with documented OTD 5.0% of all direct ED IS patients

Onset to Door Times Among IV TPA Patients Results Mean OTD 56.3 mins, DTN 84.1mins IV TPA more frequent among golden hour patients than 1-3 hour 27.1% vs 12.9%, p < 0.0001 Onset to Door Times Among IV TPA Patients N Percent < 60 mins 8111 64.7% 61-180 mins 4327 34.5% > 180 mins 107 0.9%

Results: IV TPA DTN Times DTN in all 12,545 IV TPA patients: 86 mins (SD 42) Longer DTN in golden hr patients: mean 90.6 v 76.7 mins, p < 0.0001 Inverse relation OTD – DTN times: r = - 0.30

Results DTN Time among Golden Hour Patients

Results Target DTN Time ≤ 60 Minutes Target DTN ≤ 60 mins achieved in 18.3% of golden hour-arriving patients Modest increase in proportion of patients with target DTN times by calendar year Absolute increase 1.2% per year, p=.027 Year Proportion with DTN ≤ 60 mins 2003 12.8% 2004 15.9% 2005 18.9% 2006 17.8% 2007 19.5%

Results Target DTN Time ≤ 60 Minutes No substantial increase in proportion of patients with target DTN times duration of hospital participation in GWTG-S p = 0.65 Year Participating in GWTG-S Proportion with DTN ≤ 60 mins 1 18.0% 2 18.5% 3 18.4% 4 19.0% 5 18.9%

Limitations Participation in GWTG is voluntary and may select for higher performing hospitals. Hospitals participating in GWTG-Stroke are likely to have more well-organized stroke systems of care than nonparticipating hospitals, so other US hospitals are likely on average to have worse lytic treatment rates and door to needle times than observed in this cohort. The last known well time was documented in 42% of patients. Additional factors important in fostering rapid care were not captured in the GWTG-Stroke database and therefore not analyzed, including policies of local Emergency Medical Service (EMS) agencies, hospital provision of education programs to EMS, location of CT or MRI scanners in the ED, and policies regarding need for ancillary testing before treatment such as coagulation studies, CT angiography and CT perfusion imaging, or multimodal MRI imaging, etc.

Conclusions At GWTG-S hospital ED’s, these patients arrive within 1 hour of onset symptoms: More than 1/4 of patients with documented Onset Time At least 1/8 of all Ischemic Stroke patients These Golden Hour patients: receive thrombolytic therapy more frequently but more slowly than late arrivers. Target Door-To-Needle Time of less than 60 minutes achieved in less than 1/5 of these patients The findings support public health initiatives to increase early presentation and shorten Door-to-Needle times in patients arriving within the Golden Hour.