Original Contribution
Race/Ethnic Differences in the Risk of Hemorrhagic
Complications Among Patients With Ischemic Stroke
Receiving Thrombolytic Therapy
Rajendra H. Mehta, MD, MS; Margueritte Cox, MS; Eric E. Smith, MD, MPH;
Ying Xian, MD, PhD; Deepak L. Bhatt, MD, MPH; Gregg C. Fonarow, MD;
Eric D. Peterson, MD, MPH; for the Get With The Guidelines-Stroke Program
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Background and Purpose—Race/ethnic-related differences in safety of intravenous thrombolytic therapy have been shown
in patients with myocardial infarction, but not studied in ischemic stroke.
Methods—Using data from the Get With The Guidelines (GWTG)-Stroke program (n=54 334), we evaluated differences
in risk-adjusted bleeding rates (any, symptomatic intracerebral hemorrhage [sICH], serious life-threatening [excluding
sICH], or other) and mortality in white (n=40 411), black (n=8243), Hispanic (n=4257), and Asian (n=1523) patients
receiving intravenous tissue-type plasminogen activator (tPA) for acute ischemic stroke.
Results—Compared with white patients, overall adjusted hemorrhagic complications after tPA were higher in black (odds
ratio, 1.14, 95% confidence interval, 1.04–1.28) and Asian (odds ratio, 1.36, 95% confidence interval, 1.14–1.61) patients.
Overall adjusted bleeding complications in Hispanics were similar to those of whites. Increased risk of overall bleeding
in Asians was related to higher risk of adjusted sICH (odds ratio, 1.47, 95% confidence interval, 1.19–1.82), whereas in
blacks, it was related to higher risk of other bleeding. No significant race-related difference was noted in risk of serious or
life-threatening bleeding or in overall mortality or death in patients with sICH or any hemorrhagic complications.
Conclusions—In patients with stroke receiving tPA, hemorrhagic complications were slightly higher in blacks and Asians,
but not in Hispanics compared with whites. Asians also faced significantly higher risk for sICH relative to other race/
ethnic groups. Future studies are needed to evaluate whether reduction in tPA dose similar to that used in many Asian
countries could improve the safety of tPA therapy in Asians in the United States with acute ischemic strokes while
maintaining efficacy. (Stroke. 2014;45:00-00.)
Key Word: stroke
L
Using data on patients enrolled in the Get With The
Guidelines (GWTG)-Stroke program,10–12 the goals of the current study were: (1) to determine comparative bleeding rates in
whites, blacks, Asians, and Hispanics among those receiving
intravenous tissue-type plasminogen activator (tPA) for acute
ischemic stroke; (2) to investigate whether any differences in
bleeding risk persist after adjusting for baseline clinical features; and (3) to evaluate relationships between race/ethnicity,
bleeding events, and overall and cause-specific mortality.
arge, multicenter, randomized placebo-controlled clinical trials have demonstrated that early use of intravenous
thrombolysis <4.5 hours of symptom onset reduces morbidity and mortality in selected patients with ischemic stroke.1–5
However, these pivotal trials were conducted in largely white
populations with low representation of racial or ethnic minorities. Yet, observational studies have raised concerns that the
efficacy and safety of thrombolytic therapy may vary among
racial and ethnic groups. For example, blacks treated with
intravenous thrombolytic therapy for acute ST segment elevation myocardial infarction (STEMI) have higher bleeding risk
and mortality relative to their white counterparts.6,7 In contrast,
Asians or Hispanics with STEMI have had similar responses as
whites treated with fibrinolysis.8,9 However, race-related differences in efficacy and safety of intravenous thrombolytic therapy
have not been studied among patients with ischemic stroke.
Methods
GWTG-Stroke Program, Patient Population,
and Definitions
Details of the GWTG-Stroke program, including the methods of
data collection and data definitions used, have been described previously.10–12 Data from patients hospitalized with ischemic stroke at
Received February 11, 2014; final revision received May 27, 2014; accepted May 28, 2014.
From the Department of Internal Medicine/Division of Cardiology, Duke University Medical Center and Duke Clinical Research Institute, Durham,
NC (R.H.M., M.C., Y.X., E.D.P.); Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (E.E.S.); Department of Internal Medicine/
Division of Cardiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (D.L.B.); and Department of Internal Medicine/
Division of Cardiology, University of California, Los Angeles (G.C.F.).
Correspondence to Rajendra H. Mehta, MD, Department of Internal Medicine/Division of Cardiology, Duke Clinical Research Institute, Box 17969,
2400 Pratt St, Durham, NC 27715. E-mail raj.mehta@dm.duke.edu
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.005019
1
2 Stroke August 2014
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GWTG-Stroke participating hospitals between April 1, 2009, and
April 30, 2013 (n=2 328 868; 1922 sites) were included in this analysis. Patients were excluded if they were enrolled before April 1, 2009
(n=932 048), nonischemic stroke (n=498 076), in-hospital stroke
(n=20 946), did not receive intravenous tPA (n=815 554), received
intra-arterial tPA (n=3127), received tPA under experimental protocol (n=120), or >4.5 hours of symptom onset (n=1322), those with
missing values of either race (n=136) or tPA complications (n=957),
and those belonging to race/ethnic group other than white, black,
Hispanic, or Asian (n=2248). The remaining 54 334 patients formed
the basis of this analysis.
Information on race and ethnicity was obtained from patient selfdesignation as recorded by administrative personnel during the registration process, admitting providers in the medical record, or nurses
in nursing intake forms. Race and ethnicity were collected as separate questions as recommended by the Office of Minority Health.
We then classified the responses into the categories reported. Thus,
white race/ethnicity are non-Hispanic white patients, blacks are nonHispanic blacks, Asians are non-Hispanic Asians, and Hispanic patients are those of Hispanic ethnicity irrespective of race. Bleeding
was collected in GWTG-Stroke program as complication of thrombolytic therapy and included symptomatic intracranial hemorrhage
≤36 hours (sICH) and life-threatening serious systemic hemorrhage
≤36 hours (other than sICH), and other serious bleeding. sICH within the first 36 hours of treatment was defined as any neurological deterioration with evidence of ICH on repeat brain imaging (National
Institute of Neurological Disorders and Stroke definition).5 Serious
systemic hemorrhage was defined as bleeding <36 hours of intravenous tPA (not including sICH) and >3 U of packed RBC transfusion
<7 days or before discharge (whichever was earlier), with a physician note attributing the bleeding problem as the reason for transfusion. Other serious bleeding was defined as any bleeding besides
above that required additional medical intervention(s) or prolonged
hospital stay.
Outcomes of Interests
Primary outcomes of interests were any complication of tPA (sICH,
serious systemic life-threatening hemorrhage, and other bleeding) as well as individual component of this composite end point,
and all cause in-hospital mortality (total and in patients with tPA
complication).
Statistical Analyses
Patients were categorized into 4 race/ethnicity-based groups: white,
black, Hispanic, and Asian. Other demographic (besides race/ethnicity) and clinical variables, as well as hospital-level characteristics,
were displayed. Continuous variables are reported as medians with
25th and 75th percentiles, and categorical variables as frequencies
and percentages. Univariate comparisons were performed using
Pearson χ2 test for categorical variables and Wilcoxon rank-sum test
for continuous variables.
Multivariable logistic regression analysis using generalized estimating equation (exchangeable correlation structure) to account for
within-hospital correlation was used to adjust for the confounding effect of the differences in baseline patient and hospital characteristics
between the different race/ethnic groups on outcomes of interests.
White race was used as a reference group for comparisons. Baseline
factors in addition to race/ethnicity used to account for baseline differences included age, sex, arrival mode, medical history (smoking,
diabetes mellitus, coronary artery disease or myocardial infarction,
stroke/TIA, atrial fibrillation/flutter, carotid stenosis, peripheral vascular disease, hypertension, and dyslipidemia) and findings on physical examination (time to treatment, systolic blood pressure, heart rate,
and weight). In addition, hospital-level characteristics associated with
outcomes were also included (geographic region, number of beds,
academic versus not, annual stroke volume, and percentage of minority treated). Spline transformations were generated to assess whether
continuous variables were related to outcomes in nonlinear fashion.
Imputations for missing variables were imputed as the most frequent
category for categorical variables and as median value for continuous
variables with the exception of medical history variables, which were
imputed as no. Most variables had missing rates <2%; notable exceptions included baseline features (body mass index, 27.7%; heart rate,
17.1%; systolic blood pressure, 15.1%; insurance type, 12.1%; arrival
mode, 9.5%) and laboratory data (fasting blood glucose, 22.0%; prothrombin time, 18.6%; serum creatinine, 17.3%).
We also performed a sensitivity analysis evaluating risk-adjusted
outcomes of interest (adjusting for baseline patient and hospital characteristics and National Institutes of Health Stroke Scale [NIHSS])
among patients who had the NIHSS score available (n=50 231;
92.4%). Finally, we evaluated risk-adjusted mortality in patients who
had any complication and in those who had sICH after intravenous
tPA.
Odds ratios and 95% confidence intervals were generated (reference whites). For all analyses, a 2-tailed P value <0.05 was considered statistically significant. All statistical analyses were performed
using SAS version 9.3 software (SAS Institute, Cary, NC).
Results
Patient Demographics, History, and Presentation
Among patients receiving tPA, whites were oldest relative
to the other race/ethnic group. Although statistically significantly different because of large sample size, the door
to needle time or the symptom onset to treatment time was
not clinically significantly different among the 4 groups
(Table 1). Compared with other race/ethnic groups, the
prevalence of history of atrial fibrillation, prosthetic heart
valves, coronary artery disease, peripheral vascular disease,
carotid stenosis, and dyslipidemia was highest in whites;
that of prior stroke, hypertension, congestive heart failure,
or current smoking highest in blacks; and that of diabetes
mellitus highest in Hispanics. In contrast, the prevalence of
diabetes mellitus and hypertension was lowest in whites;
atrial fibrillation lowest in blacks; and history of prosthetic
heart valve, previous stroke, coronary artery disease, carotid
stenosis, peripheral vascular disease, smoking, and heart
failure lowest in Asians. Blacks were likely to present with
the highest heart rate and systolic and diastolic blood pressures and, although they had the highest presenting serum
creatinine, their presenting estimated glomerular filtration
rate was highest given their younger age and highest body
mass index. The NIHSS was highest among Asians compared with other race/ethnic groups. Blacks were more likely
to be treated in large teaching hospitals but were least likely
to be treated at certified primary stroke centers.
In-Hospital Hemorrhagic Complications
Any observed hemorrhagic complications after tPA were
higher in Asians compared with whites and remained significantly higher even after adjustment for baseline confounding. Similarly, adjusted odds of sICH was 1.5-fold and
significantly higher among Asians compared with whites,
whereas the adjusted odds for serious or life-threatening
hemorrhage and other hemorrhagic complications was not
statistically significantly different compared with whites
(Tables 2 and 3).
Blacks too had significantly higher adjusted odds of any
hemorrhagic complications as well as other serious hemorrhagic complications compared with whites after tPA.
Adjusted odds for sICH or serious systemic life-threatening
Mehta et al Race, Stroke, Thrombolysis, and Outcomes 3
Table 1. Baseline Characteristics
Variable
n
Overall
54 334
White
40 411
Black
8243
Hispanic
4257
Asian
P Value
1523
Demographics
Age, y*
Female sex
72 (59, 82)
74 (62, 83)
62 (52, 74)
68 (56, 79)
72, 61, 81)
<0.0001
50.5
50.3
52.0
49.6
47.9
0.0051
Ambulance
82.8
83.1
83.0
80.2
83.9
0.0001
Arrival during nonregular hours
49.0
48.5
51.3
48.3
52.0
<0.0001
Arrival mode and timelines
Onset to arrival time, min*
Door to needle time, min*
Onset to treatment time, min*
59 (39, 90)
59 (40, 90)
59 (39, 90)
58 (38, 90)
57 (40, 90)
0.0579
<0.0001
73 (55, 96)
73 (55, 95)
75 (56, 99)
73 (55, 97)
70 (55, 94)
142 (112, 174)
142 (112, 174)
145 (114, 175)
142 (110. 175)
140 (108, 172)
0.0001
Medical history
Atrial fibrillation/flutter
Prosthetic heart valve
21.3
23.8
11.5
16.0
23.6
<0.0001
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1.1
1.2
0.8
0.9
0.7
0.0004
Previous stroke/TIA
25.0
24.7
27.8
24.8
19.9
<0.0001
Coronary artery disease
25.7
27.4
19.9
23.0
18.7
<0.0001
Carotid stenosis
2.8
3.3
1.2
1.5
1.1
<0.0001
Diabetes mellitus
26.2
23.5
32.6
38.1
30.0
<0.0001
3.5
3.9
2.9
2.5
1.3
<0.0001
Hypertension
73.4
71.9
79.8
74.4
76.5
<0.0001
Current smoker
18.0
16.9
26.4
14.9
9.4
<0.0001
Dyslipidemia
40.8
42.9
32.7
37.5
39.9
<0.0001
9.2
9.0
11.8
7.1
5.1
<0.0001
10 (6, 17)
10 (6, 17)
Peripheral vascular disease
Congestive heart failure
Presenting features and laboratory
NIHSS score*
Heart rate, bpm*
10 (6, 16)
11 (6, 17)
11 (6, 18)
<0.0001
80 (69, 92)
79 (69, 91)
82 (71, 95)
81 (70, 94)
79 (69, 92)
<0.0001
Systolic blood pressure, mm Hg*
154 (137, 175)
154 (137, 174)
156 (138, 179)
155 (137, 177)
155 (138, 177)
<0.0001
Diastolic blood pressure, mm Hg*
83 (72, 96)
82 (71, 94)
88 (77, 102)
84 (73, 97)
84 (72, 96)
<0.0001
Body mass index, kg/m2*
27 (24, 32)
27 (24, 31)
29 (25, 34)
28 (25, 33)
25 (22, 28)
<0.0001
Fasting blood glucose, mg/dL*
119 (102, 148)
118 (102, 145)
119 (101, 154)
128 (106, 172)
129 (109, 164)
<0.0001
Prothrombin time, INR*
1.0 (1.0, 1.1)
1.0 (1.0, 1.1)
1.0 (1.0, 1.1)
1.0 (1.0, 1.1)
1.0 (1.0, 1,1)
<0.0001
Serum creatinine, mg/dL*
1.0 (0.8, 1,30)
1.0 (0.8, 1,2)
1.1 (0.9, 1.4)
1.0 (0.8, 1.20)
1.0 (0.8, 1.20)
<0.0001
Estimated GFR, mL/min*
71 (54, 88)
69 (52, 86)
78 (58, 98)
74 (56, 94)
73 (56, 89)
<0.0001
Hospital characteristics
Teaching/academic
Rural
Number of beds*
62.8
60.6
74.9
59.3
66.2
<0.0001
3.1
3.7
1.3
0.7
3.5
<0.0001
379 (265, 561)
370 (258, 548)
445 (319, 701)
390 (280, 595)
349 (228, 489)
<0.0001
Number of stroke discharges
≥301
49.4
48.5
56.8
44.4
46.5
101–300
41.0
41.6
35.6
45.0
42.1
9.6
9.9
7.7
10.6
11.5
≤100
<0.0001
Ischemic stroke admissions/y*
212 (147, 318)
210 (144, 319)
230 (160, 319)
192 (140, 292)
212 (148, 305)
<0.0001
Volume of tPA administration/y*
18 (10, 27)
17 (10, 26)
19 (11, 29)
19 (11, 29)
18 (12, 25)
<0.0001
Primary stroke center certification
54.4
56.2
47.8
49.8
54.8
<0.0001
GFR indicates glomerular filtration rate; INR, international normalized ratio; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; and tPA,
tissue-type plasminogen activator.
*Median (25th, 75th percentile).
hemorrhagic complications were similar for blacks and
whites. In contrast, there were no differences in the adjusted
odds for any complication in Hispanics compared with
whites treated with tPA. Sensitivity analyses restricting
the patient population to that with information on NIHSS
demonstrated results directionally similar to that of overall
results for all race/ethnic comparisons relative to their white
counterparts.
4 Stroke August 2014
Table 2. Outcomes
Variable
n
Overall
White
Black
Hispanic
Asian
P Value
54 334
40 411
8243
4257
1523
Any complication
9.1
9.0
9.0
9.6
11.8
0.0022
Symptomatic intracranial hemorrhage
4.7
4.8
4.1
4.7
6.8
<0.0001
Serious/life-threatening hemorrhage
1.0
1.0
0.9
1.1
1.3
0.3568
Other
3.3
3.1
4.0
3.4
3.6
0.0004
7.8
8.2
5.7
7.3
9.6
<0.0001
Patients with intracranial hemorrhage
33.2
33.7
31.2
31.5
34.0
0.8126
Patients with any tPA complication
34.4
34.6
32.5
33.0
41.9
0.1440
4.7
5.1
2.8
4.1
5.4
<0.0001
51.1
49.4
56.2
56.3
57.7
<0.0001
46.1
45.1
48.5
51.3
43.3
<0.0001
Unable to ambulate
23.7
24.1
21.3
23.9
25.6
Ambulate with assistance
31.7
32.0
30.8
29.8
31.6
Ambulate independently
44.6
43.9
47.9
46.3
42.8
tPA complications
In-hospital mortality*
Overall
Patients without any tPA complications
Length of stay >4 d
Discharge status
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Discharged home
Discharge ambulatory status
<0.0001
tPA indicates tissue-type plasminogen activator.
*Excludes transfer outs.
Discharge Status and Mortality After tPA
Blacks were most likely whereas Asians least likely to be
ambulating independently at discharge compared with other
groups. Asians were least likely whereas Hispanics most
likely to be discharged home compared with other groups
(Tables 2 and 3).
Overall observed in-hospital mortality was lower for blacks
and Hispanics compared with whites, whereas Asians had
similar observed in-hospital death compared with whites.
However, once adjusted for baseline confounding, there were
no significant racial differences in in-hospital mortality compared with whites. These results were changed slightly once
accounted for NIHSS score (in addition to baseline and hospital characteristics), where blacks had lower adjusted odds for
death relative to whites. Among those with ICH or any hemorrhagic complications, there were no differences in adjusted
(for baseline and hospital characteristics and NIHSS) in-hospital mortality by race.
Discussion
Our study represents the largest study to date of race/ethnic
differences in the risks of hemorrhagic complications after
tPA therapy in acute ischemic stroke. Our data indicated that
adjusted overall complications after tPA were higher in both
Asian and blacks compared with white patients with stroke.
In Asians, this increase was because of higher adjusted sICH
with similar risks of life-threatening serious or other complications compared with whites. In blacks, this increased risk
of any complication after tPA was because of higher adjusted
rates of other tPA complications compared with whites.
The observed incidence of sICH was significantly lower in
blacks than in whites after tPA therapy. However, given their
younger age and lower prevalence of comorbid conditions,
once adjusted for baseline confounding, there was no significant difference in the odds of sICH in blacks compared with
whites, whereas serious or life-threatening hemorrhagic complications remained similar to that in whites. Hispanics had
similar adjusted odds of tPA complications compared with
whites.
Overall adjusted in-hospital mortality was similar by race.
Adjusted mortality in patients with sICH (or any complications) after tPA for stroke was higher than in their counterparts
without sICH (or any complications). However, in patients
with sICH (or any complications), adjusted mortality for
blacks, Hispanics, and Asians was similar to that in whites.
One prior study used the National Inpatient Sample hospital discharge database for the period of 2001 to 2008
obtained from the Healthcare Cost and Utilization Project of
the Agency of Healthcare Research and Quality and evaluated the race/ethnic disparities in the use and outcomes of
patients with stroke receiving tPA.13 This study found that
the use of tPA in patients with stroke was higher for whites
(2.3%) compared with blacks (1.8%; P<0.001) and Hispanics
(2.0%; P<0.001), whereas it was similar for whites and Asians
(2.3% versus 2.2%; P=0.07). Furthermore, they found that
ICH rates were significantly higher in Asians compared with
whites (odds ratio, 2.01; 95% confidence interval, 1.91–2.11;
P<0.001). In-hospital mortality was also significantly higher
among Asians compared with whites (odds ratio, 1.22; 95%
confidence interval, 1.03–1.44; P=0.02). In contrast, the rates
of ICH or in-hospital mortality did not differ significantly in
blacks and Hispanics compared with whites. Similarly, a previous study from the GWTG registry evaluating the predictors
of sICH in patients receiving tPA for acute stroke has shown
Mehta et al Race, Stroke, Thrombolysis, and Outcomes 5
Table 3. Adjusted Outcomes and Results of Sensitivity Analyses
Variables
Adjusted Odds Ratio*
95% Confidence Interval
P Value
Blacks
1.14
1.04, 1.28
0.007
Hispanics
1.12
0.99, 1.27
0.084
Asians
1.36
1.14, 1.61
<0.001
Blacks
1.04
0.91, 1.19
0.580
Hispanics
1.07
0.90, 1.28
0.456
Asians
1.47
1.19, 1.82
<0.001
Blacks
1.16
0.90, 1.50
0.259
Hispanics
1.19
0.81, 1.76
0.378
Asians
1.31
0.86, 2.00
0.208
Blacks
1.29
1.13, 1.47
<0.001
Hispanics
1.10
0.91, 1.32
0.343
Asians
1.14
0.84, 1.54
0.400
Blacks
0.94
0.84, 1.05
0.246
Hispanics
1.02
0.89, 1.18
0.780
Asians
1.16
0.96, 1.41
0.121
Blacks
1.08
0.97, 1.20
0.138
Hispanics
1.09
0.96, 1.25
0.189
Asians
1.25
1.03, 1.52
0.025
Blacks
1.00
0.87, 1.15
0.974
Hispanics
1.06
0.88, 1.27
0.536
Asians
1.39
1.10, 1.74
0.005
Blacks
0.87
0.67, 1.12
0.273
Hispanics
1.12
0.77, 1.64
0.559
Asians
1.33
0.84, 2.09
0.223
Blacks
1.20
1.04, 1.39
0.013
Hispanics
1.04
0.84, 1.27
0.740
Asians
1.05
0.76, 1.45
0.778
Blacks
0.86
0.77, 0.97
0.017
Hispanics
0.94
0.80, 1.10
0.444
Asians
0.93
0.74, 1.17
0.552
Overall patients (n=54 334)
Any tPA complications
Intracranial hemorrhage
Serious/life-threatening hemorrhage
Other complications of tPA
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In-hospital mortality
Patients with NIHSS data (n=50 231)
Any tPA complications
Intracranial hemorrhage
Serious/life-threatening hemorrhage
Other complications of tPA
In-hospital mortality
Death among patients with any tPA complications (n=4767)
Blacks
1.01
0.83, 1.22
0.941
Hispanics
0.97
0.74, 1.27
0.823
Asians
1.18
0.84, 1.66
0.331
Death in patients with intracranial hemorrhage after tPA (n=2576)
Blacks
0.97
0.73, 1.28
0.813
Hispanics
0.85
0.58, 1.27
0.431
Asians
0.92
0.61, 1.39
0.698
NIHSS indicates National Institutes of Health Stroke Scale; and tPA, tissue-type plasminogen activator.
*Whites for all comparisons.
6 Stroke August 2014
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Asian race (compared with non-Asian) to be associated with
an independent risk of sICH (odds ratio, 2.12; 95% confidence
interval, 1.28–3.50).14
Although some of the findings of our study were consistent
with other studies, our study allows more accurate identification of potential clinical confounders. Specifically, unlike in
study by Nasr et al,13 data on baseline prognostic clinical, presenting, and laboratory features (smoking status, body mass
index, baseline heart rate and blood pressure, time to treatment, NIHSS) were available in GTWG-Stroke initiative, thus
allowing for a relatively more robust risk adjustment in our
study compared with that by Nasr et al.13 The study evaluating
independent predictors of sICH from GWTG did not focus
specifically on the racial differences in bleeding, but rather
just reported increased odds of sICH among Asians after tPA
for acute stroke.14 Finally, our study provided additional information on race/ethnic disparities in other serious systemic
hemorrhagic complications among patients receiving tPA
(besides sICH) and in-hospital mortality associated with these
complications that were not reported in the prior studies.
The reasons for the increased risk of sICH in Asians compared with whites with strokes receiving intravenous tPA are
not known. Differences in measured confounders (including NIHSS) explained part, but failed to account fully for
the increased risk of sICH in Asians compared with whites
treated with tPA for stroke in our study. Previous studies have
suggested that a lower dose of tPA than the dose routinely
used in the United States in Asians with stroke was associated with similar efficacy but with a lower risk of intracranial
bleeding.15–18 Alternatively, given that studies in acute STEMI
population have failed to show higher risk of intracranial
bleeding among Asians compared with whites despite higher
dose of front-loaded regimen of tPA and concomitant intravenous anticoagulation,8 this may suggest that perhaps rather
than increased sensitivity to thrombolysis, weakening in the
blood vessel wall or surrounding milieu potentially related
to diffuse atherosclerosis, which increases the permeability
of RBCs across the damaged blood vessels, may account for
the higher risk of bleeding in Asian patients with stroke (who
typically are older with higher comorbid conditions) after tPA.
Our findings of no increased risk of sICH among blacks
compared with whites were also at odds with those reported
in patients with acute STEMI.6,7,19 Among patients with acute
STEMI treated with front-loaded tPA, blacks have been consistently shown to be at an increased risk of ICH as well as other
bleeding events compared with whites despite their younger age
and higher body weight. Genetically inherent enhanced sensitivity to thrombolysis has been speculated by some as the mechanism underlying the increased risk of ICH among blacks.6
However, given that no such increased risk was observed
among more elderly black patients with stroke raises the possibility that perhaps other factors including front-loading of tPA
in patients with acute STEMI (compared with a slower infusion
of tPA over a longer period in stroke patients) or the routine
concomitant intravenous anticoagulation in these patients may
explain this disparate finding in the 2 ethnic populations.
Our findings may have some implications. First, our data
suggest that as in many Asian countries where the use of lower
dose of tPA (0.6 mg/kg) <3 hours of stroke onset is a norm,15–18
this regimen may perhaps also be equally efficacious and likely
safer for Asians compared with higher dose routinely used
among white patients with stroke in the United States. This
hypothesis needs to be tested in future study. Second, efficacy
and safety of tPA for acute stroke tested and proven in large randomized trials consisting mostly of white patients should not be
presumed to be true in other race/ethnic groups because these
may vary. Enrollment of a large number of patients of diverse
race/ethnic groups in clinical trials or comparative effectiveness
studies through well-designed registries would allow better
understanding of the efficacy/effectiveness and safety of tPA in
the treatment of acute stroke in various race/ethnic groups.
Limitations
Patients and hospitals may not be entirely representative
because hospital participation in GWTG-Stroke is voluntary.
Nonetheless, the demographics of the GWTG-Stroke fee-forservice Medicare patient population are similar to the overall demographics of fee-for service Medicare patients with
stroke.20 Our study was observational and retrospective, and we
are unable to account for the influence of missing or unmeasured confounders on study findings. Therefore, we recommend
caution when inferring causal relationships from our data. We
used a definition of sICH based on the 1995 National Institute
of Neurological Disorders and Stroke trial that attributes clinical worsening to ICH documented on computerized tomography or magnetic resonance imaging based on the investigator’s
judgment. This definition is different from the European
Cooperative Acute Stroke Study (ECASS) II definition, in
which clinical deterioration is defined as a 4-point increase in
NIHSS, or the Safe Implementation of Thrombolysis in Stroke:
A Multinational Multicentre Monitoring Study of Safety and
Efficacy of Thrombolysis in Stroke (SITS-MOST) definition,
in which, in addition, only parenchymal hemorrhages type 2
can be considered symptomatic. sICH events were determined
by the treating physicians, and neuroimaging data were not
centrally reviewed. Thus, although we are unable to provide
information on the rates of bleeds and outcomes in area of
index stroke compared with those in the remote areas of the
brain, the large difference in mortality between patients with
and without sICH suggests that the sICH events were clinically
relevant. Asians were categorized as one group, but in fact
represent a heterogeneous population. Given that there was no
systematic validation that all race/ethnicity were self-reported,
it is possible that race/ethnicity group could be misclassified
including that Hispanic patients were misclassified by sites as
being non-Hispanic white or non-Hispanic black patients.
Conclusions
In patients with stroke receiving tPA, complications were
slightly higher in blacks and Asians, but not in Hispanics compared with whites. Asian patients also faced higher risk for
sICH relative to other race/ethnic groups. Future studies are
needed to evaluate whether reduction in tPA dose similar to
that used in many Asian countries could improve the safety of
tPA therapy in Asians in the United States with acute ischemic
strokes while maintaining efficacy.
Mehta et al Race, Stroke, Thrombolysis, and Outcomes 7
Sources of Funding
The Get With The Guidelines (GTWG)-Stroke program is provided by the American Heart Association (AHA)/American Stroke
Association. GTWG-Stroke has been funded in the past through
support from Boeringher-Ingelheim, Merck, Bristol Myers Squibb/
Sanofi Pharmaceutical Partnership, Janseen Pharmaceuticals, and
AHA Pharmaceutical Round.
Disclosures
Downloaded from http://stroke.ahajournals.org/ by guest on October 1, 2016
Dr Bhatt discloses the following relationships—advisory board:
Elsevier Practice Update Cardiology, Medscape Cardiology, Regado
Biosciences; board of directors: Boston VA Research Institute,
Society of Cardiovascular Patient Care; chair: American Heart
Association Get With The Guidelines Steering Committee; honoraria: American College of Cardiology (Editor, Clinical Trials,
Cardiosource), Belvoir Publications (Editor in Chief, Harvard Heart
Letter), Duke Clinical Research Institute (clinical trial steering committees), Population Health Research Institute (clinical trial steering
committee), Slack Publications (Chief Medical Editor, Cardiology
Today’s Intervention), WebMD (CME steering committees); other: Senior Associate Editor, Journal of Invasive Cardiology; data
monitoring committees: Duke Clinical Research Institute, Harvard
Clinical Research Institute, Mayo Clinic, Population Health Research
Institute; research grants: Amarin, AstraZeneca, Bristol-Myers
Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines
Company; unfunded research: FlowCo, PLx Pharma, Takeda. The
other authors report no conflicts.
References
1. Stroke Study Group. Tissue plasminogen activator for acute ischemic
stroke. N Engl J Med. 1995;333:1581–1587.
2. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al.
Intravenous thrombolysis with recombinant tissue plasminogen activator
for acute hemispheric stroke. The European Cooperative Acute Stroke
Study (ECASS). JAMA. 1995;274:1017–1025.
3. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D,
et al. Randomised double-blind placebo-controlled trial of thrombolytic
therapy with intravenous alteplase in acute ischaemic stroke (ECASS
II). Second European-Australasian Acute Stroke Study Investigators.
Lancet. 1998;352:1245–1251.
4.Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP,
Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase)
for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS
Study: a randomized controlled trial. Alteplase Thrombolysis for
Acute Noninterventional Therapy in Ischemic Stroke. JAMA.
1999;282:2019–2026.
5. Marler JR, Tilley BC, Lu M, Brott TG, Lyden PC, Grotta JC, et al. Early
stroke treatment associated with better outcome: the NINDS rt-PA stroke
study. Neurology. 2000;55:1649–1655.
6. Berkowitz SD, Granger CB, Pieper KS, Lee KL, Gore JM, Simoons M,
et al. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. The Global Utilization of
Streptokinase and Tissue Plasminogen activator for Occluded coronary
arteries (GUSTO) I Investigators. Circulation. 1997;95:2508–2516.
7. Mehta RH, Stebbins A, Lopes RD, Rao SV, Bates ER, Pieper KS, et al.
Race, bleeding, and outcomes in STEMI patients treated with fibrinolytic
therapy. Am J Med. 2011;124:48–57.
8. Mehta RH, Parsons L, Peterson ED; National Registry of Myocardial
Infarction Investigators. Comparison of bleeding and in-hospital mortality in Asian-Americans versus Caucasian-Americans with ST-elevation
myocardial infarction receiving reperfusion therapy. Am J Cardiol.
2012;109:925–931.
9.Cohen MG, Granger CB, Ohman EM, Stebbins AL, Grinfeld LR,
Cagide AM, et al. Outcome of Hispanic patients treated with thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I
and III trials. Global Utilization of Streptokinase and TPA for Occluded
Coronary Arteries. J Am Coll Cardiol. 1999;34:1729–1737.
10. Schwamm LH, Fonarow GC, Reeves MJ, Pan W, Frankel MR, Smith
EE, et al. Get With the Guidelines-Stroke is associated with sustained
improvement in care for patients hospitalized with acute stroke or transient ischemic attack. Circulation. 2009;119:107–115.
11. Fonarow GC, Reeves MJ, Smith EE, Saver JL, Zhao X, Olson DW, et al;
GWTG-Stroke Steering Committee and Investigators. Characteristics,
performance measures, and in-hospital outcomes of the first one million
stroke and transient ischemic attack admissions in get with the guidelines-stroke. Circ Cardiovasc Qual Outcomes. 2010;3:291–302.
12. Fonarow GC, Reeves MJ, Zhao X, Olson DM, Smith EE, Saver JL, et al;
Get With the Guidelines-Stroke Steering Committee and Investigators.
Age-related differences in characteristics, performance measures, treatment trends, and outcomes in patients with ischemic stroke. Circulation.
2010;121:879–891.
13. Nasr DM, Brinjikji W, Cloft HJ, Rabinstein AA. Racial and ethnic disparities in the use of intravenous recombinant tissue plasminogen activator and outcomes for acute ischemic stroke. J Stroke Cerebrovasc Dis.
2013;22:154–160.
14. Menon BK, Saver JL, Prabhakaran S, Reeves M, Liang L, Olson DM, et
al. Risk score for intracranial hemorrhage in patients with acute ischemic
stroke treated with intravenous tissue-type plasminogen activator. Stroke.
2012;43:2293–2299.
15. Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, et
al; Japan Alteplase Clinical Trial (J-ACT) Group. Alteplase at 0.6 mg/
kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase
Clinical Trial (J-ACT). Stroke. 2006;37:1810–1815.
16. Nakagawara J, Minematsu K, Okada Y, Tanahashi N, Nagahiro S, Mori
E, et al; J-MARS Investigators. Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the
Japan post-Marketing Alteplase Registration Study (J-MARS). Stroke.
2010;41:1984–1989.
17. Mori E, Minematsu K, Nakagawara J, Yamaguchi T, Sasaki M, Hirano
T; Japan Alteplase Clinical Trial II Group. Effects of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral
artery occlusion: Japan Alteplase Clinical Trial II (J-ACT II). Stroke.
2010;41:461–465.
18. Chao AC, Hsu HY, Chung CP, Liu CH, Chen CH, Teng MM, et al;
Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS)
Study Group. Outcomes of thrombolytic therapy for acute ischemic
stroke in Chinese patients: the Taiwan Thrombolytic Therapy for Acute
Ischemic Stroke (TTT-AIS) study. Stroke. 2010;41:885–890.
19.Mehta RH, Parsons L, Rao SV, Peterson ED; National Registry of
Myocardial Infarction (NRMI) Investigators. Association of bleeding
and in-hospital mortality in black and white patients with st-segmentelevation myocardial infarction receiving reperfusion. Circulation.
2012;125:1727–1734.
20. Reeves MJ, Fonarow GC, Smith EE, Pan W, Olson D, Hernandez AF, et
al. Representativeness of the Get With The Guidelines-Stroke Registry:
comparison of patient and hospital characteristics among Medicare beneficiaries hospitalized with ischemic stroke. Stroke. 2012;43:44–49.
Race/Ethnic Differences in the Risk of Hemorrhagic Complications Among Patients With
Ischemic Stroke Receiving Thrombolytic Therapy
Rajendra H. Mehta, Margueritte Cox, Eric E. Smith, Ying Xian, Deepak L. Bhatt, Gregg C.
Fonarow and Eric D. Peterson
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