emily o’brien, msph predoctoral trainee february 16, 2010 the north carolina stroke care...
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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
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Stroke Statistics
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 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).
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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
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National Institute of Neurological Disorders and Stroke (NINDS) rtPA stroke study: time interaction with favorable neurological 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
Time Window for Receipt of t-PA (1996-2007)
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Time Window for Receipt of t-PA (2009) Recent European studies examining t-PA
given from 3-4.5 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
Need for confirmation of resultsSource: 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;
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Study Aims
1) Estimate the association between use of t-PA beyond 3-hour time interval since symptom onset with
1) Length of hospital stay2) Adverse clinical outcomes
Hemorrhagic complications In-hospital death
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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
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Legend^ JC-PSC Hospitals
No Hospital CountiesNCSCC Counties
The North Carolina Stroke Care Collaborative (NCSCC)
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Study PopulationEnrolled strokes
N=39073-38045 who did not
receive t-PA
-49 transferred orobservation only
-5 with documentedt-PA contraindications
t-PA PatientsN=1028
Patients withoutcontraindications
N=1023
Final Sample Size N= 946
-28 with incomplete mortality or covariate
dataHospitalized
Patients N=974
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Exposure Definition
T-PA Timing• “Early t-PA” = receipt <3 hours since time last
known well• “Late t-PA” = receipt >3 hours since time last
known wellOutcome Definitions Length of hospital stay
Discharge date – admission date Adverse clinical outcomes
Complications: Intracerebral hemorrhage or systemic hemorrhage within 36 hoursAND/OR
In-hospital death
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Covariates
Gender Age Race (white vs. non-white) Arrival mode (EMS vs. non-
EMS) Prior history of stroke Ambulation status at time of
admission
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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)
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Clinical Characteristics of the Study Population
by Time of Administration (NCSCC: 2005-2008)
Variable.Mean or %
Early t-PA(n=744, 79%)
Late t-PA(n=202, 21%)
p-value
Mean age, years 68.0 66.5 0.22
Male (%) 50.8 46.0 0.23
Non-white (%) 26.8 26.2 0.89
Arrival mode – EMS (%) 86.0 78.2 <0.01
Mean in-hospital delay, min 78.5 134.2 <0.01
Mean prehospital delay, min 78.1 112.1 0.46
Mean length of stay, days 6.9 6.7 0.43
Documented complications (%)
7.3 6.4 0.69
Death prior to discharge (%) 12.4 10.4 0.44
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Distribution of time from symptom onset to t-PA among late t-PA patients(NCSCC 2005 – 2010)
Time to T-PA (minutes)
Nu
mb
er o
f p
atie
nts
200 250 300 3500
10
20
30
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0
1
2
3
4
5
6
7
8
Len
gth
of
stay
in
day
s(
Mea
n;
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
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Receipt of t-PA > 3 hours after symptom onset* and adverse outcomes†
(NCSCC: 2005 – 2010)
Model Description OR (95% CI)
Model 1. Unadjusted 0.80 (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
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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
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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
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Acknowledgements
CoauthorsKathryn M RoseMehul D PatelWayne 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
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Thank you!
Emily O’BrienUNC Chapel Hill
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TABLE 1. Clinical Characteristics of the Study Population. NCSCC (2005-2008)Variables Time-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)
GenderMale 378 (50.8) 93 (46.0) 0.23
Female 366 (49.3) 109 (54.0)Race
White 545 (73.3) 149 (73.8) 0.89Non-White 199 (26.8) 53 (26.2)
Arrival ModeEMS 640 (86.0) 158 (78.2) 0.007
Non-EMS 104 (14.0) 44 (21.8)Health Insurance
Private 437 (58.7) 118 (58.4) 0.93Public/None 307 (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 complicationsYes 54 (7.3) 13 (6.4) 0.69No 690 (92.7) 189 (93.6)
Expired on dischargeYes 92 (12.4) 21 (10.4) 0.44No 652 (87.6) 181 (89.6)
*Chi-squared analysis for differences in proportions
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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
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Receipt of t-PA 3 – 4.5 hours after symptom onset* and adverse outcomes†
(NCSCC: 2005 – 2010)
Model Description OR (95% CI)
Model 1. Unadjusted 0.82 (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
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Distribution of time from symptom onset to t-PA (NCSCC 2005 – 2010)
0 50 100 150 200 250 300 3500
20
40
60
80
100
120
Time to T-PA (minutes)
Nu
mb
er o
f p
atie
nts
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1
10
Early tPA
Late tPA
Model 1. Crude
Model 2. Age, sex,
race
Model 3. Model 2 + Arrival mode,
ambulation status
Mea
n d
ays
( lo
g t
ran
sfo
rme
d;
95%
CI)
Association between timing of receipt of t-PA and length of stay: NSCCC (2005 – 2010).
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Distribution of time from symptom onset to t-PA among early t-PA patients(NCSCC 2005 – 2010)
Time to T-PA (minutes)
Nu
mb
er o
f p
atie
nts
0 50 100 150 2000
50
100
150