Emily O’Brien, MSPH Predoctoral Trainee February 16, 2010 The North Carolina Stroke Care Collaborative Clinical Outcomes among Stroke Patients Receiving t-PA Beyond the Recommended Time Window

Stroke Statistics 3 rd leading cause of death in the U.S. 3 rd leading cause of death in the U.S. Stroke prevalence is 5,700,000 Stroke prevalence is 5,700,000 –Males: 2.3 million –Females: 3.4 million Per year: Per year: –600,000 new strokes –180,000 recurrent strokes Estimated direct and indirect cost of $65.5 billion Estimated direct and indirect cost of $65.5 billion Effective early management of acute ischemic strokes may lead to better outcomes Effective early management of acute ischemic strokes may lead to better outcomes Source:Rosamond, W. et al. Heart Disease and Stroke Statistics—2008 Update. A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117 (4): e25 (2008).

Tissue Plasminogen Activator (t-PA) FDA-approved treatment for ischemic strokes (1996) FDA-approved treatment for ischemic strokes (1996) Catalyzes conversion of plasminogen to plasmin Catalyzes conversion of plasminogen to plasmin Associated with Associated with Increased survival Increased survival Reduced disability Reduced disability Improved neurological outcomes Improved neurological outcomes Hyperfibrinolysis  increased risk of hemorrhage Hyperfibrinolysis  increased risk of hemorrhage Administration within 3 hours  used infrequently because of prehospital patient delays Administration within 3 hours  used infrequently because of prehospital patient delays

National Institute of Neurological Disorders and Stroke (NINDS) rtPA stroke study: time interaction with favorable neurological outcomes at 3 months National Institute of Neurological Disorders and Stroke (NINDS) rtPA stroke study: time interaction with favorable neurological outcomes at 3 months minutes: OR= 2.11 (1.33 – 3.55) minutes: OR= 2.11 (1.33 – 3.55) minutes: OR= 1.69 (1.09 – 2.62) minutes: OR= 1.69 (1.09 – 2.62) 2007: American Heart Association(AHA)/ American Stroke Association(ASA) recommend administration within 3 hours of symptom onset 2007: American Heart Association(AHA)/ American Stroke Association(ASA) recommend administration within 3 hours of symptom onset Time Window for Receipt of t-PA ( )

Time Window for Receipt of t-PA (2009) Recent European studies examining t-PA given from hours after symptom onset Recent European studies examining t-PA given from hours after symptom onset 1)ECASS-3 Trial: No increased mortality vs. <3 hours 2)SITS-MOST Registry: No differences in mortality, complications, modified Rankin score May 2009: AHA/ASA recommend administration up to 4.5 hours for patients without contraindications May 2009: AHA/ASA recommend administration up to 4.5 hours for patients without contraindications Need for confirmation of results Need for confirmation of results Source: Del Zoppo, et al. on behalf of the AHA Stroke Council: Expansion of the Time Window for treatment of Acute Ischemic Stroke with Intravenous Tissue Plasminogen Activator: A Science Advisory From the American Heart Association/American Stroke Association. Stroke 2009;40; ;

Study Aims 1) Estimate the association between use of t-PA beyond 3-hour time interval since symptom onset with 1) Length of hospital stay 2) Adverse clinical outcomes  Hemorrhagic complications  In-hospital death

One of six Paul Coverdell National Acute Stroke Registries established to measure, track, and improve the quality of stroke care One of six Paul Coverdell National Acute Stroke Registries established to measure, track, and improve the quality of stroke care 53 participating hospitals representing 63% of all stroke discharges in NC 53 participating hospitals representing 63% of all stroke discharges in NC N=39073 participants enrolled from January 2005 – January 2010 N=39073 participants enrolled from January 2005 – January 2010 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Legend ^ JC-PSC Hospitals No Hospital Counties NCSCC Counties The North Carolina Stroke Care Collaborative (NCSCC)

Study Population Enrolled strokes N= who did not receive t-PA -49 transferred or observation only -5 with documented t-PA contraindications t-PA Patients N=1028 Patients without contraindications N=1023 Final Sample Size N= with incomplete mortality or covariate data Hospitalized Patients N=974

Exposure Definition T-PA Timing T-PA Timing “Early t-PA” = receipt <3 hours since time last known well “Early t-PA” = receipt <3 hours since time last known well “Late t-PA” = receipt >3 hours since time last known well “Late t-PA” = receipt >3 hours since time last known well Outcome Definitions Length of hospital stay Length of hospital stay Discharge date – admission date Discharge date – admission date Adverse clinical outcomes Adverse clinical outcomes Complications: Intracerebral hemorrhage or systemic hemorrhage within 36 hours Complications: Intracerebral hemorrhage or systemic hemorrhage within 36 hoursAND/OR In-hospital death In-hospital death

Covariates Gender Gender Age Age Race (white vs. non-white) Race (white vs. non-white) Arrival mode (EMS vs. non-EMS) Arrival mode (EMS vs. non-EMS) Prior history of stroke Prior history of stroke Ambulation status at time of admission Ambulation status at time of admission

Statistical Methods Chi-squared test statistics for differences in proportions Chi-squared test statistics for differences in proportions Regression analyses Regression analyses –Multivariable linear regression to estimate adjusted length of stay for early and late t-PA patients –Multivariable logistic regression to estimate odds ratios (OR) and 95% CIs for the association between time of administration and adverse outcomes –Robust variance estimators to account for clustering within hospitals All analyses performed using SAS v. 9.1 (SAS Institute, Cary, NC) All analyses performed using SAS v. 9.1 (SAS Institute, Cary, NC)

Clinical Characteristics of the Study Population by Time of Administration (NCSCC: ) Variable. Mean or % Early t-PA (n=744, 79%) Late t-PA (n=202, 21%) p-value Mean age, years Male (%) Non-white (%) Arrival mode – EMS (%) <0.01 Mean in-hospital delay, min <0.01 Mean prehospital delay, min Mean length of stay, days Documented complications (%) Death prior to discharge (%)

Distribution of time from symptom onset to t-PA among late t-PA patients (NCSCC 2005 – 2010) Time to T-PA (minutes) Number of patients

Length of stay in days ( Mean; 95% CI) Model 1. Crude Model 2. Age, sex, race Model 3. Model 2 + Arrival mode, ambulation status Association between timing of receipt of t-PA and length of stay: NSCCC (2005 – 2010) Early t-PA Late t-PA

Receipt of t-PA > 3 hours after symptom onset* and adverse outcomes † (NCSCC: 2005 – 2010) Model Description OR (95% CI) Model 1. Unadjusted0.80 (0.52, 1.25) Model 2. Model 1 + age, race, gender 0.81 (0.52, 1.27) Model 3. Model 2 + ambulatory status on admission, mode of arrival 0.82 (0.52, 1.30) * Early t-PA patients were administered t-PA within 3 hours of the documented last known well time † Adverse oucomes defined as complications including symptomatic intracranial hemorrhage or serious systemic hemorrhage or in-hospital death

Summary Patients receiving t-PA beyond 3 hours from symptom onset were less likely to arrive by EMS and had longer in-hospital delays Patients receiving t-PA beyond 3 hours from symptom onset were less likely to arrive by EMS and had longer in-hospital delays We did not detect differences in length of stay or odds of hemorrhagic complications or death between early and late t-PA patients We did not detect differences in length of stay or odds of hemorrhagic complications or death between early and late t-PA patients

Conclusions Our results are consistent with clinical trials that report no increased risk of complications or mortality at discharge with use of t-PA beyond 3 hours Our results are consistent with clinical trials that report no increased risk of complications or mortality at discharge with use of t-PA beyond 3 hours Future research should examine the association between time of administration, neurological status after discharge, and long-term survival Future research should examine the association between time of administration, neurological status after discharge, and long-term survival

Acknowledgements Coauthors Coauthors Kathryn M Rose Kathryn M Rose Mehul D Patel Mehul D Patel Wayne D Rosamond Wayne D Rosamond Staff and participants of the North Carolina Stroke Care Collaborative for their important contributions Staff and participants of the North Carolina Stroke Care Collaborative for their important contributions Support of the NHLBI National Research Award Training Grant Support of the NHLBI National Research Award Training Grant

Thank you! Emily O’Brien UNC Chapel Hill

TABLE 1. Clinical Characteristics of the Study Population. NCSCC ( ) VariablesTime-eligible (n = 744, 79%) Time Ineligible (n = 202, 21%) Pvalue* Mean Age (95% CI)68.0 (66.9, 69.1)66.5 (64.4, 68.6) Gender Male378 (50.8)93 (46.0)0.23 Female366 (49.3)109 (54.0) Race White545 (73.3)149 (73.8)0.89 Non-White199 (26.8)53 (26.2) Arrival Mode EMS640 (86.0)158 (78.2)0.007 Non-EMS104 (14.0)44 (21.8) Health Insurance Private437 (58.7)118 (58.4)0.93 Public/None307 (41.3)84 (41.6) Time to administration (min)134.7 (132.4, 137.6)250.1 (224.3, 276.0) Length of stay, Days (95% CI)6.9 (6.4, 7.4)6.7 (5.8, 7.6) Documented complications Yes54 (7.3)13 (6.4)0.69 No690 (92.7)189 (93.6) Expired on discharge Yes92 (12.4)21 (10.4)0.44 No652 (87.6)181 (89.6) *Chi-squared analysis for differences in proportions

Figure. SICH and mortality in observational studies and randomised trials with alteplase in ischaemic strokeFigure shows mean and 95% CI. NR=not reported. *Median age except in STARS (mean). †Patients who did not meet inclusion/exclusion criteria were systematically excluded. ‡SICH according to NINDS definition: NIHSS ≥1 and any haemorrhage on CT at 24– 36h.2 §3-month mortality except for STARS (1 month). Alteplase and mortality in observational studies and RCTs

Receipt of t-PA 3 – 4.5 hours after symptom onset* and adverse outcomes † (NCSCC: 2005 – 2010) Model Description OR (95% CI) Model 1. Unadjusted0.82 (0.52, 1.30) Model 2. Model 1 + age, race, gender 0.82 (0.52, 1.31) Model 3. Model 2 + ambulatory status on admission, mode of arrival 0.81 (0.51, 1.31) * Early t-PA patients were administered t-PA within 3 hours of the documented last known well time † Adverse oucomes defined as complications including symptomatic intracranial hemorrhage or serious systemic hemorrhage or in-hospital death

Distribution of time from symptom onset to t-PA (NCSCC 2005 – 2010) Time to T-PA (minutes) Number of patients

Model 1. Crude Model 2. Age, sex, race Model 3. Model 2 + Arrival mode, ambulation status Mean days ( log transformed; 95% CI) Association between timing of receipt of t-PA and length of stay: NSCCC (2005 – 2010).

Distribution of time from symptom onset to t-PA among early t-PA patients (NCSCC 2005 – 2010) Time to T-PA (minutes) Number of patients