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Original Article

Low-Dose versus Standard-Dose Intravenous

Alteplase in Acute Ischemic Stroke
C.S. Anderson, T. Robinson, R.I. Lindley, H. Arima, P.M. Lavados, T.-H. Lee,
J.P. Broderick, X. Chen, G. Chen, V.K. Sharma, J.S. Kim, N.H. Thang, Y. Cao,
M.W. Parsons, C. Levi, Y. Huang, V.V. Olavarra, A.M. Demchuk, P.M. Bath,
G.A. Donnan, S. Martins, O.M. Pontes-Neto, F. Silva, S. Ricci, C. Roffe,
J. Pandian, L. Billot, M. Woodward, Q. Li, X. Wang, J. Wang, and J. Chalmers,
for the ENCHANTED Investigators and Coordinators*

A BS T R AC T
BACKGROUND

Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose

of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage.
METHODS

Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients

who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to lowdose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose
(0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the
onset of stroke. The primary objective was to determine whether the low dose would
be noninferior to the standard dose with respect to the primary outcome of death or
disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin
scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine
whether the low dose would be superior to the standard dose with respect to centrally
adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be
noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also
randomly assigned to intensive or guideline-recommended blood-pressure control.

The authors full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr.
Anderson at the George Institute for
Global Health, Royal Prince Alfred Hospital, Sydney Health Partners, and the University of Sydney, P.O. Box M201, Missenden Rd., Sydney, NSW, Australia, or at
[email protected].
*A complete list of sites and trial investigators and coordinators in the Enhanced
Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) is provided in the Supplementary Appendix,
available at NEJM.org.
This article was published on May 10,
2016 at NEJM.org.
DOI: 10.1056/NEJMoa1515510
Copyright 2016 Massachusetts Medical Society.

RESULTS

The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose
group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio,
1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P = 0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds
ratio, 1.00; 95% CI, 0.89 to 1.13; P = 0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in
2.1% of the participants in the standard-dose group (P = 0.01); fatal events occurred
within 7 days in 0.5% and 1.5%, respectively (P = 0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P = 0.07).
CONCLUSIONS

This trial involving predominantly Asian patients with acute ischemic stroke did
not show the noninferiority of low-dose alteplase to standard-dose alteplase with
respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National
Health and Medical Research Council of Australia and others; ENCHANTED
ClinicalTrials.gov number, NCT01422616.)
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hrombolytic therapy with intravenous alteplase (recombinant tissue-type

plasminogen activator) at a dose of 0.9 mg
per kilogram of body weight is an effective treatment for acute ischemic stroke, despite increasing
the risk of intracerebral hemorrhage.1-3 However,
the Japanese drug safety authority has approved
the use of alteplase at a dose of 0.6 mg per kilogram after an uncontrolled, open-label study
showed that this dose resulted in equivalent clinical outcomes and a lower risk of intracerebral
hemorrhage than that reported in published studies in which the 0.9-mg-per-kilogram dose was
used.4 Other registry studies in Asia5-11 have shown
inconsistent results, but a high risk of symptomatic intracerebral hemorrhage was observed among
Asian patients treated with 0.9 mg of alteplase per
kilogram in the United States.12 Differing perceived
risks of intracerebral hemorrhage and treatment
affordability have led to variations in the doses of
intravenous alteplase used to treat patients with
acute ischemic stroke in Asia.8-11
The Enhanced Control of Hypertension and
Thrombolysis Stroke Study (ENCHANTED) was
designed to compare low-dose with standard-dose
intravenous alteplase in patients with acute ischemic stroke. Using a quasi-factorial design, we are
also assessing the effects of early intensive lowering of blood pressure as compared with guideline-recommended management in patients with
elevated blood pressure; this part of the trial is
scheduled to be completed in 2018. We report the
results of the alteplase part of the trial, which was
completed in December 2015.

Me thods
Trial Design and Oversight

In an international, multicenter, prospective, randomized, open-label trial with blinded outcome

evaluation, two doses of intravenous alteplase were
compared in patients with an acute ischemic
stroke who were eligible for thrombolytic therapy;
administration of the drug was commenced within
4.5 hours after the onset of the stroke. Patients
with elevated systolic blood pressure (range, 150 to
220 mm Hg) could also be randomly assigned to
early and intensive lowering of blood pressure (target systolic blood pressure <140 mm Hg within
1 hour) or conventional guideline-directed management of blood pressure (target systolic blood
pressure <180 mm Hg) with the use of locally
available intravenous agents.
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Details of the design and statistical analysis

plan of the trial have been published previously.13,14
An international steering committee, whose members designed the trial with an advisory committee, was responsible for the conduct and reporting of the trial. The George Institute for Global
Health coordinated the trial, managed the database, and performed the analyses. The study drug
used (alteplase) was that available for routine use
at clinical centers; there was no commercial input
into any aspect of the trial. The first author wrote
the first and subsequent drafts of the manuscript.
All the authors commented on drafts of the manuscript, approved the decision to submit the manuscript for publication, and vouch for the accuracy
and completeness of the data and for the fidelity
of this report to the trial protocol (available with
the full text of this article at NEJM.org).
The trial protocol was approved by all appropriate regulatory authorities and ethics committees at the participating centers. All participants,
or an approved surrogate for those who were too
unwell to comprehend the information, provided
written informed consent. Details of the monitoring procedures are provided in the Supplementary Appendix (available at NEJM.org).
Patients and Procedures

Patients were recruited at 111 clinical centers in

13 countries. Patients were eligible if they were
18 years of age or older, had an acute ischemic
stroke, and met guideline-recommended criteria
for treatment with intravenous alteplase. For details of the inclusion and exclusion criteria, see
the Supplementary Appendix.
After confirmation of patient eligibility, randomization was performed centrally with the use
of a minimization algorithm according to center,
time from stroke onset (<3 vs. 3 hours), and severity of neurologic impairment (score of <10 vs.
10 on the National Institutes of Health Stroke
Scale [NIHSS]; range, 0 to 42, with higher scores
indicating greater severity of stroke). Participants
were randomly assigned to receive either a standard dose of intravenous alteplase (0.9 mg per kilogram of estimated, or measured, body weight;
10% as a bolus and 90% as an infusion over a period of 60 minutes; maximum dose, 90 mg) or a
low dose (0.6 mg per kilogram, 15% as a bolus and
85% as an infusion over a period of 60 minutes;
maximum dose, 60 mg), to be commenced within
4.5 hours after symptom onset. Concomitant
therapy followed national practice guidelines, innejm.org

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Low-Dose versus Standard-Dose Intr avenous Alteplase

cluding the use of endovascular thrombectomy

devices, where approved.
Demographic and clinical data were obtained
at the time of randomization. Follow-up data were
obtained at 24 and 72 hours (including repeat
NIHSS scores and measured body weight) and at
7 days (or hospital discharge, if sooner), 28 days,
and 90 days, unless death occurred earlier. The
28-day and 90-day evaluations were conducted in
person or by telephone, by trained and certified
staff who remained unaware of the randomized
treatment assignments. Brain imaging was performed at trial entry and at 24 hours, and additionally if clinically indicated, and was analyzed centrally for any hemorrhage by expert assessors who
were unaware of the treatment assignments
(see the Supplementary Appendix).

related quality of life on the EuroQoL Group

5-Dimension Self-Report Questionnaire (EQ-5D;
summary health utility scores range from 0.109
to 1, with higher scores indicating better health)18
at 90 days (for details on scoring, see the Supplementary Appendix), length of initial hospital stay,
recurrent acute myocardial infarction and recurrent ischemic stroke, admission to a long-term
residential care facility at 90 days, and use of
health services (for economic analyses that have
not yet been conducted). Prespecified safety outcomes were all serious adverse events reported
until trial completion. Tertiary outcomes included
all-cause mortality, place of death, trends in modified Rankin scale scores during follow-up, length
of stay in the intensive care unit (ICU), rate of
thrombectomy, and individual items of the EQ-5D.

Outcomes

Statistical Analysis

The prespecified primary outcome was the combined end point of death or disability at 90 days,
which was defined by scores of 2 to 6 on the
modified Rankin scale,15 a global seven-level measure of functioning in which scores of 0 or 1 indicate a good outcome with no or minimal neurologic symptoms, scores of 2 to 5 indicate a poor
outcome with increasing degree of disability, and
6 indicates death. The key secondary outcome,
which was also designated as a safety outcome,
was intracerebral hemorrhage, defined according
to criteria from a number of other studies (see the
Supplementary Appendix); the main definition of
intracerebral hemorrhage that we used was the
definition in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST)16:
a large local or remote parenchymal pattern
(>30% of the infarcted area affected by hemorrhage, with mass effect or extension outside the
infarct) and neurologic deterioration from baseline (increase of 4 points in the NIHSS score)
or death within 36 hours. This definition was
finalized and described in the statistical analysis
plan of our trial after publication of the original
protocol.
Other secondary efficacy outcomes were the
distribution of modified Rankin scale scores at
90 days,17 major disability (modified Rankin scale
score >2) at 90 days, deaths at 7 days and 90 days,
neurologic deterioration (increase of 4 points
in the NIHSS score) during the 72 hours after
randomization, death and neurologic deterioration (increase of 4 points in the NIHSS score)
during the 72 hours after randomization, health-

We designed the trial to assess the effects of two

treatment variables alteplase dose and intensity of blood-pressure control on clinical outcomes, accounting for their potential interaction.14
Differential patient recruitment resulted in the
part of the trial dealing with alteplase dose being completed faster than the part dealing with
intensity of blood-pressure control. For the primary analysis, we used an unadjusted logisticregression model to test whether low-dose alteplase was noninferior to the standard dose. To
satisfy the noninferiority hypothesis, the upper
boundary of the 95% confidence interval for the
odds ratio of the outcome with low-dose alteplase
as compared with standard-dose alteplase had to
fall below a margin of 1.14; this noninferiority
margin was derived from a Cochrane meta-analyses of alteplase trials with effects on poor outcomes reported.19,20 We estimated that a sample
size of 3300 patients would provide at least 90%
power to evaluate noninferiority, assuming 5%
dropout and potential negative interaction between intensive blood-pressure control and lowdose alteplase, and would also provide at least 80%
power to detect superiority of low-dose alteplase
in achieving a 40% lower risk of symptomatic
intracerebral hemorrhage than that with standarddose alteplase, with 5% dropout. Consistency of
treatment effect across 10 prespecified subgroups
was assessed through tests for interaction.
A secondary efficacy analysis was a comparison of ordinal scores on the modified Rankin
scale to test for the noninferiority of the low dose
to the standard dose with the use of ordinal lo-

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Table 1. Characteristics of the Patients at Baseline and Their Treatment.*

Low-Dose
Alteplase
(N = 1654)

Variable

Standard-Dose
Alteplase
(N = 1643)

Age yr
Median
IQR
Female sex no. (%)

68

67

5876

5876

634 (38.3)

614 (37.4)

Region of recruitment no. (%)

China

708 (42.8)

711 (43.3)

United Kingdom, continental Europe, or Australia

445 (26.9)

439 (26.7)

Asia, other than China

336 (20.3)

334 (20.3)

South America
Asian race no./total no. (%)

165 (10.0)

159 (9.7)

1043/1651 (63.2)

1036/1640 (63.2)

1031/1648 (62.6)

1034/1640 (63.0)

Medical history no./total no. (%)

Hypertension
Any stroke

287/1654 (17.4)

302/1643 (18.4)

Coronary artery disease

256/1648 (15.5)

223/1640 (13.6)

Atrial fibrillation

330/1645 (20.1)

306/1640 (18.7)

Diabetes mellitus

325/1648 (19.7)

321/1640 (19.6)

Hypercholesterolemia

297/1648 (18.0)

258/1640 (15.7)

Current cigarette use

377/1646 (22.9)

393/1638 (24.0)

Modified Rankin scale score of 0 before stroke

1349/1647 (81.9)

1325/1639 (80.8)

Use of antihypertensive agent

755/1648 (45.8)

743/1640 (45.3)

Use of statin or other lipid-lowering agent

333/1646 (20.2)

282/1638 (17.2)

Use of aspirin or other antiplatelet agent

407/1647 (24.7)

345/1638 (21.1)

48/1647 (2.9)

34/1638 (2.1)

14920

15020

Warfarin anticoagulation
Blood pressure mm Hg
Systolic
Diastolic

8413

8513

8 (514)

8 (514)

Signs of cerebral ischemia on brain imaging no./total no. (%)

388/1648 (23.5)

383/1640 (23.4)

Proximal vessel occlusion on CTA or MRA no./total no. (%)

258/1622 (15.9)

248/1624 (15.3)

NIHSS score median (IQR)

Final diagnosis at time of hospital discharge no./total no. (%)**

Nonstroke diagnosis

50/1625 (3.1)

47/1609 (2.9)

Large-artery occlusion due to clinically significant atheroma

622/1625 (38.3)

648/1609 (40.3)

Small-vessel or perforator lacunar disease

334/1625 (20.6)

339/1609 (21.1)

Cardioembolism

324/1625 (19.9)

317/1609 (19.7)

Dissection
Other or uncertain cause of stroke

14/1625 (0.9)

11/1609 (0.7)

281/1625 (17.3)

247/1609 (15.4)

170

170

Time from stroke onset to alteplase administration min

Median
IQR
Estimated body weight before alteplase administration kg

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127219

69.614.4

69.914.4

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Low-Dose versus Standard-Dose Intr avenous Alteplase

Table 1. (Continued.)

Variable

Low-Dose
Alteplase
(N = 1654)

Standard-Dose
Alteplase
(N = 1643)

Any alteplase given to patients no. (%)

1628 (98.4)

1617 (98.4)

Bolus dose mg

6.21.2

6.32.1

Infusion dose mg

35.57.3

56.011.3

460 (27.8)

475 (28.9)

Assigned to intensive blood-pressure lowering

224 (13.5)

232 (14.1)

Assigned to standard blood-pressure lowering

236 (14.3)

243 (14.8)

Concurrent inclusion in part of trial dealing with blood-pressure control no. (%)

* Plusminus values are means SD. There were no significant differences between trial groups in the characteristics
listed, except in the administered dose of alteplase as a bolus (P = 0.05) and as an infusion (P<0.001). CTA denotes
computed tomographic angiography, IQR interquartile range, and MRA magnetic resonance angiography.
Race was self-reported.
Medical history was based on self-report, with the exception of the presence of atrial fibrillation, which was based on
findings on electrocardiography performed at the time of presentation.
The modified Rankin scale evaluates global disability; scores range from 0 (no symptoms) to 6 (death).
Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating
more severe neurologic deficits. Scores ranged from 0 to 40 in the low-dose group and from 0 to 42 in the standarddose group.
This finding was reported by clinician investigators.
** Diagnoses were determined by clinician investigators.
Times ranged from 28 to 1673 minutes (0.47 to 27.88 hours) in the low-dose group and from 11 to 1678 minutes
(0.18 to 27.97 hours) in the standard-dose group.

gistic regression, after the assumption of proportionality of the odds was confirmed in a likelihood-ratio test.17 A new assumption-free approach21
was used to confirm the conclusion. We also
performed secondary analyses of the primary
outcome with adjustment for minimization and
key prognostic covariates14, as well as secondary
analyses in the per-protocol population according
to criteria outlined in the Supplementary Appendix. Multiple imputation was to be used if more
than 10% of observations were missing. An independent data and safety monitoring board monitored the trial progress and safety with the use
of formal stopping boundaries. For ease of interpretation, all reported P values for noninferiority
are multiplied by 2 so that an alpha of 0.05 can
be used in analyses. The other P values (those for
superiority) are two-sided. All P values were prespecified not to be adjusted. SAS software, version
9.3 (SAS Institute), was used for analyses.

in the Supplementary Appendix); 1654 patients

were assigned to low-dose alteplase and 1643 to
standard-dose alteplase. There were no significant
differences between the low-dose group and the
standard-dose group in baseline demographic
and clinical characteristics (Table 1, and Table S2
in the Supplementary Appendix), nor in the number of patients assigned to each of the bloodpressure-lowering groups. The median age of
the patients was 67 years (14% were 80 years of
age), and 38% were women. Approximately two
thirds of the patients were Asian, and 43% were
recruited from China. The median NIHSS score
before treatment was 8 (range, 0 to 42; interquartile range, 5 to 14), and the median time
from stroke onset to randomization was 2.7 hours
(interquartile range, 2.0 to 3.5).
Interventions

In both groups, the mean time from the onset

of stroke to administration of alteplase was 170
minutes; the mean dose of alteplase adminisR e sult s
tered as an infusion was 35.5 mg in the low-dose
Patients
group and 56.0 mg in the standard-dose group
From March 2012 through August 2015, a total (P<0.001) (Table 1). The distribution of dosing
of 3310 of the 69,325 patients who were screened and the protocol violations are outlined in Figunderwent randomization (Fig. S1 and Table S1 ure S2 and Tables S3 and S4 in the Supplemenn engl j med

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tary Appendix. Postrandomization management,

including endovascular thrombectomy and rates
of recanalization, was similar in the two groups
during the first 7 days (Table S5 in the Supplementary Appendix). Outcome at 90 days was
assessed by telephone in 84.6% of the patients in
the low-dose group and in 83.6% of the patients
in the standard-dose group; the rest of the patients were assessed by in-person examination.
The sources of information for the modified
Rankin scale scores were balanced between the
groups (Table S6 in the Supplementary Appendix).
Blood-Pressure Control

In the part of the trial dealing with blood-pressure control that included 935 patients with elevated systolic blood pressure (range, 150 to 220
mm Hg), 224 patients in the low-dose group
(13.5%) and 232 in the standard-dose group (14.1%)
were assigned to rapid blood-pressure reduction.
In both alteplase dose groups, the mean systolic
blood pressure levels were significantly lower, by
7 to 9 mm Hg, with intensive blood-pressure
control than with standard blood-pressure management at 1 hour and 6 hours after randomization (Table S7 in the Supplementary Appendix).
Primary Outcome

Scores on the modified Rankin scale for assessment of the primary outcome could not be obtained, owing to withdrawal of consent or loss
to follow-up, in 47 of the patients assigned to
low-dose alteplase and 44 assigned to standarddose alteplase (Fig. S1 in the Supplementary Appendix). In the modified intention-to-treat analysis, the primary outcome (scores of 2 to 6 on the
modified Rankin scale) occurred in 855 of 1607
patients (53.2%) in the low-dose group and in
817 of 1599 patients (51.1%) in the standard-dose
group (odds ratio, 1.09; 95% confidence interval
[CI], 0.95 to 1.25; the upper boundary of the 95%
confidence interval exceeded the prespecified
boundary for noninferiority of 1.14; one-sided
P = 0.51 for noninferiority) (Table 2, and Fig. S3
in the Supplementary Appendix). In an adjusted
analysis of the intention-to-treat population, the
rate was 53.3% in the low-dose group and 50.9%
in the standard-dose group (odds ratio, 1.13;
95% CI, 0.97 to 1.31; P = 0.88 for noninferiority);
in an adjusted analysis in the per-protocol population, the rates were 53.5% and 51.3%, respectively (odds ratio, 1.13; 95% CI, 0.96 to 1.32;
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one-sided P = 0.89 for noninferiority). There was

no heterogeneity of effect between patients who
began alteplase treatment less than 3 hours after
stroke onset and those who began treatment 3 or
more hours after stroke onset (Fig. S5 in the
Supplementary Appendix), and there was no significant interaction between intensity of bloodpressure lowering and alteplase dose (P = 0.29).
Secondary Outcomes

In an unadjusted ordinal analysis of the distribution of modified Rankin scale scores in the two
groups, the odds ratio with low-dose alteplase as
compared with standard-dose alteplase was 1.00
(95% CI, 0.89 to 1.13; P = 0.04 for noninferiority)
(Table 2). The assumption-free, adjusted, and perprotocol alternative approaches were consistent
in showing no significant difference in the treatment effect for overall functional outcome on the
modified Rankin scale between doses of alteplase
(Fig. 1, and Figs. S3, S4, and S6 and Tables S8, S9,
and S10 in the Supplementary Appendix).
Major symptomatic intracerebral hemorrhage
according to SITS-MOST criteria occurred in 17 of
1654 patients (1.0%) in the low-dose group and
in 35 of 1643 patients (2.1%) in the standard-dose
group (odds ratio, 0.48; 95% CI, 0.27 to 0.86;
P = 0.01) (Table 2). There was no significant interaction between intensive blood-pressure lowering and alteplase dose group with respect to the
risk of major symptomatic intracerebral hemorrhage (P = 0.71). Symptomatic intracerebral hemorrhage according to other criteria also occurred
significantly less frequently in the low-dose group
than in the standard-dose group (Table 2, and
Fig. S7 in the Supplementary Appendix); for example, the rate of fatal events within 7 days was
0.5% in the low-dose group and 1.5% in the
standard-dose group (odds ratio, 0.37; 95% CI,
0.17 to 0.80; P = 0.01). There was no heterogeneity in the effect of alteplase dose on the risk of
symptomatic intracerebral hemorrhage between
Asians and non-Asians (Fig. S8 in the Supplementary Appendix).
Mortality at 7 days was 3.6% in the low-dose
group versus 5.3% in the standard-dose group
(odds ratio, 0.67; 95% CI, 0.48 to 0.94; P = 0.02),
and mortality at 90 days was 8.5% versus 10.3%
(odds ratio, 0.80; 95% CI, 0.63 to 1.01; P = 0.07)
(Fig. S9 and Table S11 in the Supplementary Appendix). No significant between-group differences were evident in other secondary outcomes
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n engl j med

817/1599 (51.1)

35 (2.1)
131 (8.0)
397/1599 (24.8)
385/1599 (24.1)
225/1599 (14.1)
181/1599 (11.3)
154/1599 (9.6)
87/1599 (5.4)
170/1599 (10.6)
592/1599 (37.0)
170 (10.3)
0.640.41
43/1476 (2.9)
10 (5 to 18)
192 (11.7)
448 (27.3)

855/1607 (53.2)

17 (1.0)
98 (5.9)
403/1607 (25.1)
349/1607 (21.7)
250/1607 (15.6)
211/1607 (13.1)
165/1607 (10.3)
89/1607 (5.5)
140/1607 (8.7)
605/1607 (37.6)
140 (8.5)
0.640.40
36/1513 (2.4)
10 (5 to 17)
177 (10.7)
415 (25.1)

Low-Dose Alteplase Standard-Dose Alteplase

(N = 1654)
(N = 1643)

1.03 (0.89 to 1.19)

0.80 (0.63 to 1.01)
0.00 (0.03 to 0.03)
0.81 (0.52 to 1.27)
0.47 (1.93 to 1.00)
0.91 (0.73 to 1.12)
0.89 (0.76 to 1.04)

0.48 (0.27 to 0.86)

0.73 (0.55 to 0.95)
1.00 (0.89 to 1.13)**

1.09 (0.95 to 1.25)

Odds Ratio with Low-Dose Alteplase

(95% CI)

0.73
0.07
0.86
0.36
0.53
0.37
0.16

0.01
0.02

P Value

0.04

0.51

P Value for
Noninferiority

Plusminus values are means SD. CI denotes confidence interval.

The P values are for the comparison of the low-dose group with the standard-dose group.
The noninferiority margin was 1.14 (i.e., an upper boundary of the 95% confidence interval for the odds ratio with low-dose alteplase as compared with standard-dose alteplase of less than 1.14).
Disability was defined by a score of 2 to 5 on the modified Rankin scale, with higher scores indicating a greater degree of disability. Death was defined by a modified Rankin scale score of 6.
The main definition of symptomatic intracerebral hemorrhage used in the study was the definition from the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITSMOST): a large local or remote parenchymal intracerebral hemorrhage (>30% of the infarcted area affected by hemorrhage with mass effect or extension outside the infarct) in combination with neurologic deterioration from baseline (increase of 4 in in the NIHSS score) or death within 36 hours.
Symptomatic intracerebral hemorrhage was also assessed according to National Institute of Neurological Diseases and Stroke (NINDS) trial criteria: any intracerebral hemorrhage
with neurologic deterioration (increase of 1 in the NIHSS score) from baseline or death within 36 hours.
** The common odds ratio was estimated from an ordinal logistic-regression model and indicates the odds of a decrease of 1 in the modified Rankin scale score, with a common odds
ratio greater than 1 favoring standard-dose alteplase.
Major disability was defined by a score of 3 to 5 on the modified Rankin scale.
The EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) covers five domains of health-related quality of life: mobility, self-care, usual activities, paindiscomfort, and anxietydepression. Scores from these levels are combined to provide an overall health utility score ranging from 0.109 to 1, with higher scores indicating better health. Data were available for 1594 patients in the low-dose group and 1591 patients in the standard-dose group.
Shown in the estimated difference with 95% confidence interval.
Neurologic deterioration was defined as an increase from baseline of at least 4 in the NIHSS score.
Serious adverse events were defined by standard criteria and included those that resulted in death, were life-threatening, required inpatient hospitalization or prolongation of an existing hospitalization, resulted in persistent or substantive disability or incapacity, or resulted in a medical or surgical intervention to prevent permanent impairment to body structure or
function. Details on serious adverse events are provided in Table S12 in the Supplementary Appendix.

Primary outcome: death or disability no./total no. (%)

Secondary outcomes
Symptomatic intracerebral hemorrhage no. (%)
By SITS-MOST criteria
By NINDS criteria
Score on the modified Rankin scale no./total no. (%)
0: No symptoms at all
1: No substantive disability despite symptoms
2: Slight disability
3: Moderate disability requiring some help
4: Moderatesevere disability requiring assistance with daily
living
5: Severe disability, bed-bound and incontinent
6: Death
Death or major disability no./total no. (%)
Death within 90 days no. (%)
Overall health utility score on the EQ-5D
Admission to residential care no./total no. (%)
Median duration of hospitalization (IQR) days
Death or neurologic deterioration in 72 hr no. (%)
Serious adverse event no. (%)

Outcome

Table 2. Primary and Secondary Outcomes at 3 Months.*

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The

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of

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Score on Modified Rankin Scale

0

Low-Dose Alteplase

25.1

Standard-Dose Alteplase

24.8

10

21.7

15.6

24.1

20

30

50

13.1

14.1

40

60

10.3

11.3

9.6

70

80

5.5

5.4

8.7

10.6

90

100

Percent of Patients

Figure 1. Functional Outcomes at 90 Days, According to Score on the Modified Rankin Scale.
Shown is the raw distribution of scores on the modified Rankin scale at 90 days in the group that received a low
dose of alteplase (0.6 mg per kilogram of body weight) and the group that received the standard dose of alteplase
(0.9 mg per kilogram). Scores on the modified Rankin scale range from 0 to 6, with 0 indicating no symptoms,
1 symptoms without clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe
disability, 5 severe disability, and 6 death.

(Table 2). Other outcomes, including length of

Discussion
stay in the ICU, recurrent vascular events, and
individual components of the EQ-5D, are not In patients with acute ischemic stroke who met
reported here.
guideline-recommended criteria for thrombolytic
reperfusion treatment, a dose of 0.6 mg of alSubgroup Analyses
teplase per kilogram was not shown to be nonThere was no significant heterogeneity of treat- inferior to a dose of 0.9 mg of alteplase per kiloment effect on the primary outcome across gram with respect to the primary outcome of death
prespecified subgroups (Fig. 2). The interaction or disability at 90 days. Our trial was driven by
between alteplase dose and aspirin or other anti- concern about high risks of intracerebral hemorplatelet therapy was not significant (P = 0.05); rhage with alteplase, particularly among Asians,
however, this interaction was significant (P = 0.02) because preliminary studies have had differing
in a post hoc unadjusted ordinal analysis of modi- results with respect to the effectiveness and risks
fied Rankin scale scores (Fig. S10 in the Supple- of this treatment.8,11 Using several definitions of
mentary Appendix). Post hoc analyses showed symptomatic intracerebral hemorrhage,22 we obconsistency in the effect of alteplase dose on served fewer clinically important cases in the
death at 90 days across subgroups and no clear group assigned to low-dose alteplase than in the
relation with baseline NIHSS score (Fig. S11 and group assigned to standard-dose alteplase, and
S12 in the Supplementary Appendix).
the difference in risk was consistent in Asians
and non-Asians.
Safety
The distribution of modified Rankin scale
There was no significant difference between the scores in the two groups at 90 days indicates
low-dose group and the standard-dose group in that the lower rate of death with low-dose althe overall reported rate of serious adverse events, teplase than with standard-dose alteplase was
which occurred in 25.1% and 27.3% of the pa- accompanied by more patients surviving with
tients, respectively (P = 0.16). However, signifi- mild to moderately severe grades of residual discantly fewer patients in the low-dose alteplase ability. There was no heterogeneity of treatment
group than in the standard-dose alteplase group effect on the primary outcome in prespecified
had (unadjudicated) fatal cerebral hemorrhage subgroups, but these analyses had low statistical
events (1.3% vs. 2.5%, P = 0.02). All serious adverse power. One fifth of our trial population were reevents are listed in Table S12 in the Supplemen- ceiving antiplatelet therapy. Previous studies have
tary Appendix.
shown an increased risk of intracerebral hemor8

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Low-Dose versus Standard-Dose Intr avenous Alteplase

Subgroup

Low-Dose
Alteplase

Standard-Dose
Alteplase

Odds Ratio (95% CI)

P Value for
Interaction

no. (%)
Age
<65 yr
65 yr
Sex
Male
Female
Race
Asian
Non-Asian
Time from stroke onset to randomization
<3 hr
3 hr
Baseline systolic blood pressure
150 mm Hg
>150 mm Hg
Baseline NIHSS score
8
>8
Final diagnosis of ischemic stroke
Large-artery atheroma occlusion
Small-vessel disease
Cardioembolism
Other definite or uncertain cause
Cerebral infarction on CT
Yes
No
Use of antiplatelet agent
Yes
No
Evidence of atrial fibrillation
Yes
No

0.20
302 (43.9)
553 (60.2)

301 (44.3)
516 (56.1)

0.98 (0.791.22)
1.18 (0.981.42)

503 (50.9)
352 (57.0)

480 (48.0)
337 (56.4)

1.12 (0.941.34)
1.02 (0.821.29)

527 (51.5)
328 (56.4)

500 (49.0)
317 (54.7)

1.10 (0.931.31)
1.07 (0.851.35)

536 (54.5)
319 (51.1)

497 (51.8)
320 (50.1)

1.12 (0.931.34)
1.04 (0.841.30)

404 (50.6)
451 (55.7)

402 (51.6)
415 (50.6)

0.96 (0.791.17)
1.23 (1.011.49)

282 (34.9)
573 (71.8)

282 (34.6)
535 (68.3)

1.01 (0.831.24)
1.18 (0.951.46)

356 (58.0)
114 (34.4)
212 (67.5)
138 (51.1)

362 (56.7)
110 (33.0)
193 (61.7)
117 (49.2)

1.05 (0.841.32)
1.07 (0.771.47)
1.29 (0.931.79)
1.08 (0.761.53)

205 (58.9)
649 (51.7)

220 (58.0)
597 (48.9)

1.04 (0.771.39)
1.12 (0.951.31)

222 (56.3)
632 (52.3)

204 (60.7)
612 (48.5)

0.84 (0.621.12)
1.16 (0.991.36)

249 (66.9)
603 (49.1)

233 (68.3)
584 (46.4)

0.94 (0.691.28)
1.11 (0.951.30)

0.53

0.82

0.63

0.08

0.31

0.88

0.66

0.05

0.34

0.5

1.0

Low-Dose
Alteplase Better

2.0

Standard-Dose
Alteplase Better

Figure 2. Effects of Low-Dose Alteplase as Compared with Standard-Dose Alteplase on the Primary Efficacy Outcome, According to
Prespecified Subgroups.
The primary efficacy outcome was death or disability at 90 days, defined by scores of 2 to 6 on the modified Rankin scale (range,
0 [no symptoms] to 6 [death]). Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher
scores indicating more severe neurologic deficits. For subcategories, black squares represent point estimates (with the area of the
square proportional to the number of events), and horizontal lines represent 95% confidence intervals. For systolic blood pressure
and NIHSS score, values are equal to or above the median of distribution versus below the median of distribution. CT denotes
computed tomography.

rhage with standard-dose alteplase among patients receiving antiplatelet therapy.23,24 In our
prespecified analysis, there was no significant
interaction between alteplase dose and antiplatelet treatment with respect to a poor outcome;
however, the interaction was significant in a post
hoc ordinal analysis of modified Rankin scale
scores. The ongoing part of this trial is testing
n engl j med

the effectiveness of intensive and early reduction

of elevated systolic blood pressure on outcomes
in patients with ischemic stroke. Analyses did
not indicate any significant interaction between
early intensive blood-pressure lowering and alteplase dose.
Efforts to minimize reporting biases in this
open-label trial included the measurement of
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The

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body weight, blinded central adjudication of in- secondary outcome of symptomatic intracerebral
tracerebral hemorrhage, and blinded evaluation hemorrhage.
of clinical outcomes with the use of established
Presented at the European Stroke Organization Conference,
criteria. Imprecision in estimates of the treatBarcelona, May 1012, 2016.
ment effect may have arisen from interobserver
Supported by the National Health and Medical Research
variability in determining the scores on the Council of Australia, the Stroke Association of the United Kingmodified Rankin scale,15,25 which was adminis- dom, the National Council for Scientific and Technological Development of Brazil, and the Ministry for Health, Welfare, and
tered principally by telephone. Analysis of the net Family Affairs of South Korea.
change in functional outcome was based on equal
Dr. Anderson reports receiving fees for serving on advisory
weights assigned to each score (0 through 6) on boards from Medtronic and AstraZeneca and lecture fees and
travel support from Takeda. Dr. Robinson reports receiving
the modified Rankin scale, but patient and pro- personal fees from Bayer, Boehringer Ingelheim, and Daiichi
vider assessments can vary across health transi- Sankyo. Dr. Lindley reports receiving fees for serving on a steertions,26 and functional recovery can continue be- ing committee from Boehringer Ingelheim and lecture fees from
Pfizer and Covidien. Dr. Lavados reports receiving grant support
yond 90 days.27 In our trial, selection bias was and personal fees from Bayer and AstraZeneca and travel supdue to the inclusion of patients who had a pre- port from Bayer and Boehringer Ingelheim. Dr. Broderick redominantly mild severity of neurologic impair- ports fees paid to his institution for serving on a steering committee from Genentech. Dr. Demchuk reports receiving fees for
ment and who were treated at a later time point continuing medical education events from Medtronic. Dr. Bath
1,3,4
after symptom onset than in other trials and reports receiving fees for serving on a data monitoring committhan in quality-assurance studies12,16,28 of the use tee from ReNeuron, consulting fees from Athersys and Nestle,
and lecture fees from Phagenesis. Dr. Donnan reports serving
of alteplase in patients with acute ischemic stroke. on advisory boards for AstraZeneca, Boehringer Ingelheim,
The high percentage of Asian participants and Bristol-Myers Squibb, and Merck Sharp & Dohme. Dr. Ricci reconcurrent intensive blood-pressure control in ports receiving travel support from Bayer and Boehringer Ingelheim. Dr. Roffe reports receiving support from Boehringer Insome patients may also raise concerns about gelheim to organize a conference at her institution. Dr.
generalizability, despite the finding that there were Woodward reports receiving fees for serving on a data monitorno significant interactions observed between ing committee from Novartis and consulting fees from Amgen.
Dr. Chalmers reports receiving lecture fees and grant support
Asians and non-Asians, nor with intensity of from Servier. No other potential conflict of interest relevant to
blood-pressure control.
this article was reported.
Disclosure forms provided by the authors are available with
In conclusion, in a group of predominantly
the full text of this article at NEJM.org.
Asian patients with acute ischemic stroke who
We thank the patients who participated in this trial and their
were eligible for thrombolysis reperfusion thera- relatives; the clinical and research teams of the various emerpy, a dose of alteplase of 0.6 mg per kilogram gency departments, intensive care units, stroke units, and neurology departments; the George Clinical teams in Australia and
was not shown to be noninferior to the standard China; the staff of Apollo Medical Imaging Technology in Meldose of 0.9 mg per kilogram with respect to the bourne, Australia, for their assistance with the MIStar software
primary outcome of death and disability. Fewer used in the computed tomographic analyses; and Shoichiro Sato
for comments on drafts of the manuscript. The interactive voicepatients treated with low-dose alteplase than activated system used for the randomization process in China
with standard-dose alteplase (1% vs. 2%) had the was developed by Beijing MedSept Consulting.
Appendix
The authors full names and academic degrees are as follows: Craig S. Anderson, M.D., Ph.D., Thompson Robinson, M.D., Richard I.
Lindley, M.D., Hisatomi Arima, M.D., Ph.D., Pablo M. Lavados, M.D., M.P.H., Tsong-Hai Lee, M.D., Ph.D., Joseph P. Broderick, M.D.,
Xiaoying Chen, B.Pharm., B.Mgt., Guofang Chen, M.D., Vijay K. Sharma, M.D., Jong S. Kim, M.D., Ph.D., Nguyen H. Thang, M.D.,
Yongjun Cao, M.D., Ph.D., Mark W. Parsons, M.D., Ph.D., Christopher Levi, M.D., Yining Huang, M.D., Vernica V. Olavarra, M.D.,
Andrew M. Demchuk, M.D., Philip M. Bath, F.R.C.P., D.Sc., Geoffrey A. Donnan, M.D., Sheila Martins, M.D., Octavio M. Pontes-Neto,
M.D., Federico Silva, M.D., Stefano Ricci, M.D., Christine Roffe, M.D., Jeyaraj Pandian, M.D., D.M., Laurent Billot, M.Sc., Mark Woodward, Ph.D., Qiang Li, M.Biostat., Xia Wang, M.Med., Jiguang Wang, M.D., Ph.D., and John Chalmers, M.D., Ph.D.
From the George Institute for Global Health (C.S.A., R.I.L., H.A., X.C., L.B., M.W., Q.L., X.W., J.C.) and Sydney Medical School
(C.S.A., R.I.L., H.A., X.C., L.B., M.W., Q.L., J.C.), University of Sydney, and the Neurology Department, Royal Prince Alfred Hospital,
Sydney Health Partners (C.S.A.), Sydney, the Neurology Department, John Hunter Hospital, and Hunter Medical Research Institute,
University of Newcastle, Newcastle, NSW (M.W.P., C.L.), and the Florey Institute of Neuroscience and Mental Health, Parkville, VIC
(G.A.D.) all in Australia; the George Institute China, Peking University (C.S.A.), and the Department of Neurology, Peking University First Hospital (Y.H.), Beijing, the Department of Neurology, Xuzhou Central Hospital, Xuzhou (G.C.), the Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou (Y.C.), and the Shanghai Institute of Hypertension, Rui Jin Hospital,
Shanghai Jiaotong University School of Medicine, Shanghai (J.W.) all in China; the University of Leicester, Department of Cardiovascular Sciences and National Institute of Health Research Biomedical Research Unit, Leicester (T.R.), the Stroke Trials Unit, Division of
Clinical Neuroscience, University of Nottingham, Nottingham (P.M.B.), the Department of Neurosciences, Royal Stoke University
Hospital, Stoke-on-Trent (C.R.), and the George Institute for Global Health, University of Oxford, Oxford (M.W.) all in the United

10

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Low-Dose versus Standard-Dose Intr avenous Alteplase

Kingdom; the Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan (H.A.);
Clinica Alemana de Santiago, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo (P.M.L., V.V.O.), and Departamento de
Ciencias Neurolgicas, Facultad de Medicina, Universidad de Chile (P.M.L.), Santiago, Chile; the Department of Neurology, Linkou
Chang Gung Memorial Hospital, Taoyuan, Taiwan (T.-H.L.); the Departments of Neurology and Rehabilitation Medicine and Radiology,
University of Cincinnati Neuroscience Institute, University of Cincinnati Academic Health Center, Cincinnati (J.P.B.); the Division of
Neurology, Department of Medicine, National University Hospital and School of Medicine, National University of Singapore, Singapore
(V.K.S.); the Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, South Korea (J.S.K.); the Department of Cerebrovascular Disease, Peoples 115 Hospital, Ho Chi Minh City, Vietnam (N.H.T.); Calgary Stroke Program, Department of Clinical
Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada (A.M.D.); the Stroke Division of
Neurology Service, Hospital de Clnicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre (S.M.), and the Stroke
Service, Neurology Division, Department of Neuroscience and Behavior, Ribeiro Preto School of Medicine, University of So Paulo, So
Paulo (O.M.P.-N.) both in Brazil; the Neurovascular Sciences Group, Neurosciences Department, Bucaramanga, Colombia (F.S.);
Unita Operativa de Neurologia, USL Umbria 1, Sedi di Citt di Castello e Branca, Italy (S.R.); the Department of Neurology, Christian
Medical College, Ludhiana, India (J.P.); and the Department of Epidemiology, Johns Hopkins University, Baltimore (M.W.).

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