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 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).

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

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)

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 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;2945-2948;

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

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)

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

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

Covariates

Gender Age Race (white vs. non-white) Arrival mode (EMS vs. non-

EMS) Prior history of stroke Ambulation status at time of

admission

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)

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 0.22Male (%) 50.8 46.0 0.23Non-white (%) 26.8 26.2 0.89Arrival mode – EMS (%) 86.0 78.2 <0.0

1Mean in-hospital delay, min 78.5 134.2 <0.0

1Mean prehospital delay, min 78.1 112.1 0.46Mean length of stay, days 6.9 6.7 0.43Documented complications (%)

7.3 6.4 0.69

Death prior to discharge (%) 12.4 10.4 0.44

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

Time to T-PA (minutes)

Num

ber o

f pat

ient

s

200 250 300 3500

10

20

30

0

1

2

3

4

5

6

7

8

Leng

th o

f sta

y in

day

s( M

ean;

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-PALate t-PA

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

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

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

Acknowledgements Coauthors

Kathryn 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

Thank you!

Emily O’BrienUNC Chapel Hill

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)Gender

Male 378 (50.8) 93 (46.0) 0.23Female 366 (49.3) 109 (54.0)

RaceWhite 545 (73.3) 149 (73.8) 0.89

Non-White 199 (26.8) 53 (26.2)Arrival Mode

EMS 640 (86.0) 158 (78.2) 0.007Non-EMS 104 (14.0) 44 (21.8)

Health InsurancePrivate 437 (58.7) 118 (58.4) 0.93

Public/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

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. 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

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)

Num

ber o

f pat

ient

s

1

10

Early tPA

Late tPA

Model 1. Crude

Model 2. Age, sex,

race

Model 3. Model 2 + Arrival mode,

ambulation status

Mea

n da

ys( l

og tr

ansf

orm

ed; 9

5% C

I)

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)

Num

ber o

f pat

ient

s

0 50 100 150 2000

50

100

150