Emily O’Brien, MSPH Predoctoral Trainee February 16, 2010

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

2. Stroke Statistics 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). • 3rd leading cause of death in the U.S. • Stroke prevalence is 5,700,000 • Males: 2.3 million • Females: 3.4 million • Per year: • 600,000 new strokes • 180,000 recurrent strokes • Estimated direct and indirect cost of $65.5 billion • Effective early managementof acute ischemic strokes may lead to better outcomes

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

4. Time Window for Receipt of t-PA (1996-2007) • National Institute of Neurological Disorders and Stroke (NINDS) rtPA stroke study: time interaction with favorableneurological outcomes at 3 months • 0 - 90 minutes: OR= 2.11 (1.33 – 3.55) • 90 - 180 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

5. Time Window for Receipt of t-PA (2009) 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;2945-2948; • Recent European studies examining t-PA given from 3-4.5 hours after symptom onset • ECASS-3 Trial: No increased mortality vs. <3 hours • 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 • Need for confirmation of results

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

7. 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 N=39073 participants enrolled from January 2005 – January 2010 The North Carolina Stroke Care Collaborative (NCSCC) ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Legend ^ JC-PSC Hospitals No Hospital Counties NCSCC Counties

8. Study Population Enrolled strokes N=39073 -38045 who did not receive t-PA t-PA Patients N=1028 -5 with documented t-PA contraindications Patients without contraindications N=1023 -49 transferred or observation only -28 with incomplete mortality or covariate data Hospitalized Patients N=974 Final Sample Size N= 946

9. Exposure Definition T-PATiming “Early 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 • Discharge date – admission date • Adverse clinical outcomes • Complications: Intracerebral hemorrhage or systemic hemorrhage within 36 hours • AND/OR • In-hospital death

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

11. Statistical Methods Chi-squared test statistics for differences in proportions 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)

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

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

15. Receipt of t-PA > 3 hours after symptom onset* and adverse outcomes†(NCSCC: 2005 – 2010) * 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

16. Summary • 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

17. 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 • Future research should examine the association between time of administration, neurological status after discharge, and long-term survival

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

19. Emily O’Brien UNC Chapel Hill Thank you!

20. *Chi-squared analysis for differences in proportions

21. 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

22. Receipt of t-PA 3 – 4.5 hours after symptom onset* and adverse outcomes†(NCSCC: 2005 – 2010) * 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

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

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

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