Evidence that Tenecteplase Is Noninferior to Alteplase

for Acute Ischemic Stroke

Meta-Analysis of 5 Randomized Trials
Adrian M. Burgos, MD; Jeffrey L. Saver, MD

Background and Purpose—TNK (tenecteplase), a newer fibrinolytic agent, has practical delivery advantages over ALT
(alteplase) that would make it a useful agent if noninferior in acute ischemic stroke treatment outcome. Accordingly,
the most recent US American Heart Association/American Stroke Association acute ischemic stroke guideline
recognized TNK as an alternative to ALT, but only based on informal consideration, rather than formal meta-analysis,
of completed randomized control trials.
Methods—Systematic literature search and formal meta-analysis were conducted per PRISMA guidelines (Preferred Reporting
Items for Systemic Reviews and Meta-Analyses), adapted to noninferiority analysis. The primary outcome of freedom from
disability (modified Rankin Scale score, 0–1) outcome at 3 m, and additional efficacy and safety outcomes, were analyzed.
Results—Systematic search identified 5 trials enrolling 1585 patients (828 TNK, 757 ALT). Across all trials, mean age
was 70.8, 58.5% male, baseline National Institutes of Health Stroke Scale mean 7.0, and time from last known well
to treatment start mean 148 minutes. All ALT patients received standard 0.9 mg/kg dosing, while TNK dosing was
0.1 mg/kg in 6.8%, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%. For the primary end point, crude cumulative rates
of disability-free (modified Rankin Scale score, 0–1) 3 m outcome were TNK 57.9% versus ALT 55.4%. Informal,
random-effects meta-analysis, the risk difference was 4% (95% CI, −1% to 8%). The lower 95% CI bound fell well
within the prespecified noninferiority margin. Similar results were seen for the additional efficacy end points: functional
independence (modified Rankin Scale score, 0–2): crude TNK 71.9% versus ALT 70.5%, risk difference 2% (95% CI,
−3% to 6%); and modified Rankin Scale shift analysis, common odds ratio 1.21 (95% CI, 0.93–1.57). For safety end
points, lower event rates reduced power, but point estimates were also consistent with noninferiority
Conclusions—Accumulated clinical trial data provides strong evidence that TNK is noninferior to ALT in the treatment of
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acute ischemic stroke. These findings provide formal support for the recent guideline recommendation to consider TNK
an alternative to ALT.   (Stroke. 2019;50:2156-2162. DOI: 10.1161/STROKEAHA.119.025080.)
Key Words: fibrinolytic agent ◼ half-life ◼ myocardial infarction ◼ tissue-type plasminogen activator ◼ tenecteplase

T NK (tenecteplase), a genetically modified variant of ALT

(alteplase), is a newer generation fibrinolytic agent with
ease of administration advantages over ALT itself. TNK has
a higher specificity for fibrin, a longer half-life, and reduced
binding to PAI-1 (plasminogen activator inhibitor)-1 which
leads to greater resistance to inactivation by PAI-1.1 Its phar-
macokinetic profile allows TNK to be administered as a single
bolus. TNK is an established treatment for acute myocardial
infarction, where in head-to-head trials against ALT it has
shown equal therapeutic efficacy and fewer major bleeding
complications compared with ALT.2,3
TNK is a promising agent for acute ischemic stroke (AIS).
With its greater fibrin specificity, TNK theoretically has the
potential to be superior in efficacy and safety compared with
ALT for AIS. However, even if only equivalent to, rather than
better than ALT, TNK would still be a useful agent for AIS.
Since TNK requires only a one-time bolus for administration,
compared with the 60 minutes continuous infusion required
for ALT, TNK could be administered more efficiently in large
vessel occlusion patients, permitting faster start of subsequent
endovascular mechanical thrombectomy, especially in drip-
and-ship patients who could have lytic administered at an out-
side hospital and then be immediately transferred in a standard
advanced life support ambulance staffed by paramedics, rather
than having to await the availability of a critical care transport
ambulance staffed by nurses knowledgeable in continuous

Received February 15, 2019; final revision received May 6, 2019; accepted May 24, 2019.
From the Comprehensive Stroke Center and Department of Neurology, Geffen School of Medicine at UCLA, CA.
Guest Editor for this article was Louis Caplan, MD.
Presented in part at the International Stroke Conference, Honolulu, HI, February 6–8, 2019.
The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.119.025080.
Correspondence to Adrian M. Burgos, MD, Comprehensive Stroke Center and Department of Neurology, Geffen School of Medicine at UCLA, 710
Westwood Plaza, Los Angeles, CA 90095, Email jsaver@mednet.ucla.edu or Jeffrey L. Saver, MD, Comprehensive Stroke Center and Department of
Neurology, Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095, Email aburgos@mednet.ucla.edu
© 2019 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str DOI: 10.1161/STROKEAHA.119.025080

2156
 Burgos and Saver   Tenecteplase is Noninferior to Alteplase   2157
infusion pump management. TNK has been investigated for
AIS in several randomized trials, both against supportive care
and against ALT as an active comparator.
The most recent AIS guideline of the American Heart/
Stroke Association advanced a new recommendation that
TNK could be considered as an alternative to ALT in select
patients with AIS with minor neurological impairment and no
major intracranial occlusion.4 However, this recommendation
was based on informal consideration, rather than formal meta-
analysis, of completed randomized control trials. Accordingly,
we undertook a formal, noninferiority meta-analysis.
Methods
The authors declare that all supporting data are available within the
article (and its in the online-only Data Supplement) and the cited pub-
lished randomized trials.
This formal meta-analysis was conducted in accordance with
the PRISMA guidelines (Preferred Reporting Items for Systemic
Reviews and Meta-Analyses).5 We searched PubMed (Jan 2005 to
August 2018) using the search strategy tenecteplase AND alteplase
AND acute ischemic stroke. Studies were included if they met the
following criteria: (1) randomized clinical trial; (2) patients enrolled
with acute cerebral ischemia, with brain imaging performed before
enrollment to exclude hemorrhage; (3) allocation to TNK versus
active comparator ALT; and (4) treatment initiated acutely, within 6
hours after last known well time.
The primary efficacy end point analyzed was disability-free out-
come (modified Rankin Scale [mRS] score, 0–1) at 3 months post-
stroke. Additional efficacy outcomes were functional independence
(mRS, 0–2) at 3 months and reduced level of disability overall 7 mRS
levels (shift analysis) at 3 months. Safety outcomes were sympto-
matic intracranial hemorrhage (sICH) and mortality. Symptomatic
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hemorrhage events in individual trials were identified using the sICH
definition employed in that trial. Two raters (Dr Burgos and Dr Saver)
independently abstracted end point data, and any discrepancies were
resolved by consensus review.
In the lead statistical analysis, the noninferiority margin was set
at 6.5%, as per a recent major noninferiority design trial of differ-
ent fibrinolytic regimens for AIS.6 In addition, 2 more stringent non-
inferiority margins were explored: 5%, based on an older survey of
stroke experts to establish the minimally clinically important differ-
ence for stroke therapies7; and 1.3%, based on a more recent stroke
expert survey that was designed to mitigate anchoring and centrality
bias.8 Noninferiority margins were set at the same values for the
mRS 0 to 2 efficacy end point. For shift analysis, the noninferiority
margins applied to the meta-analytic common odds ratio (cOR) for
improved outcome overall 7 mRS levels was established using the
outcome distribution in the ALT group, applying 6.5%, 5%, and 1.3%
improvements at the mRS 2 to 1 transition, and then applying exactly
proportionate improvements at all other mRS transitions (yielding
thresholds of cOR 0.87, cOR 0.89, and cOR 0.97). For mortality and
sICH, the noninferiority margins were set at 1%, based on known
provider and patient intolerance of outcome differences in both these
major safety end points, and for sICH, the low rate base rate with
ALT treatment.
The meta-analytic software employed was RevMan 5.3. For the
1 trial that had multiple comparisons (2 TNK dose tiers versus same
ALT control group), unit-of-analysis error was avoided by splitting
the shared control group into 2 half-sized groups.9 Both random and
fixed effects analyses were performed. The random-effects analyses
were considered the lead approach, as they make fewer assumptions.
The fixed effects analyses, which are less subject to small trial over-
weighting, were considered sensitivity analyses.9
Results
The systematic literature search yielded 81 records for detailed
screening, among which 5 were independent randomized trials
meeting study entry criteria, (Figure I in the online-only Data
Supplement). These trials enrolled a total of 1585 patients,
(828 TNK, 757 ALT). Trial characteristics are shown in the
Table. Across all trials, mean age was 70.8, 58.8% of patients
were male, mean National Institutes of Health Stroke Scale
(NIHSS) at baseline was 7, and mean time from last known
well to treatment start was 148 minutes. Risk of bias was in-
termediate to low for all studies (Figure II in the online-only
Data Supplement). All patients with ALT received standard
0.9 mg/kg ALT dosing, 10% as a bolus, followed by the re-
maining 90% over 60 minutes. TNK dosing was one-time
bolus only, at doses of 0.1 mg/kg in 6.8% of patients, 0.25 mg/
kg in 24.6%, and 0.4 mg/kg in 68.6%.
For the primary end point freedom from disability (mRS,
0–1) at 3 m, data were available from all 5 trials, on 1585
patients (Figure 1). Crude cumulative rates of disability-free
outcome were TNK 57.9% versus ALT 55.4%. Informal, ran-
dom-effects meta-analysis, the risk difference was 4% (95%
CI, −1% to 8%). The lower 95% CI bound of −1% fell within
the lead noninferiority margin of −6.5%, as well as within the
more stringent noninferiority margins of −5% and −1.3%.
There was no evidence of modification of treatment effect by
TNK dose level, I2=0%, interaction P=0.38, although testing
for heterogeneity of the lowest, 0.1 mg/kg dose tier was under-
powered, as the low dose tier accounted for only 4.3% of the
data when weighted by SE. Considering the remaining dose
tiers, both the 0.25 mg/kg dose alone and the 0.4 mg/kg dose
alone met the lead noninferiority criterion. There was no ev-
idence of modification of treatment effect by enrollment in a
trial with no or uncommon use of concomitant endovascular
thrombectomy or a trial with planned thrombectomy for all
patients (Figure III in the online-only Data Supplement).
Considering the secondary efficacy analyses, for the ad-
ditional efficacy end point of functional independence (mRS,
0–2) at 3 m, data were available on 1473 patients from 4 tri-
als (Figure 2). Crude cumulative rates of independence were
TNK 71.9% versus ALT 70.5%, risk difference 8% (95% CI,
−4% to 20%). The lower 95% CI bound of −4 fell within the
lead noninferiority margin of −6.5%, as well as within the
more stringent noninferiority margin of −5%, but crossed
the most stringent noninferiority margin of −1.3%. No effect
modification by concomitant nonuse or use of endovascular
thrombectomy was noted (Figure IV in the online-only Data
Supplement). For the end point of level of disability at 3 m
across all 7 levels of the mRS, data were available for 1397
patients from 3 trials. Crude summary distributions combining
all trials are shown in Figure 3A and showed nominally more
highly desirable outcomes (mRS, 0 and mRS, 0–1) with TNK
versus ALT with relatively similar outcome rates for other
mRS thresholds. Formal meta-analysis of the cOR for less dis-
abled outcome found overall cOR, 1.21 (95% CI, 0.93–1.57),
with the lower bound meeting criteria for noninferiority on the
lead and the intermediate stringent thresholds, but crossing the
most stringent noninferiority margin of 0.97 (Figure 3B).
For the safety end point of symptomatic ICH, data were
available for 1585 patients from all 5 trials. Crude summary
sICH rates were TNK 3% versus ALT 3%, risk difference
0% (95% CI, –1% to 2%; Figure V in the online-only Data
Supplement). For death, in 1585 patients from all 5 trials,
 2158  Stroke  August 2019

Table.  Characteristics of Included Trials

TNK-S2B Australian TNK ATTEST Nor-Test EXTEND-IA TNK

Countries United States Australia Scotland Norway Australia and New
Zealand
Number of sites 10 3 1 13 13
Patients, n 112 75 96 1100 202
TNK dose(s), mg/kg 0.1/0.25/0.4 0.1/0.25 0.25 0.4 0.25
Age, mean (SD) 69.1 (16.6) 70 (8.23) 71 (12.5) 71 (13.8) 71.1 (14.4)
Sex, male 58 (51.8%) 39 (52%) 30.5 (31.8%) 660 (60%) 110 (54.5%)
Severity (NIHSS), mean (SD) TNK 0.1: 8 (5–11); 14.4 (2.3) TNK: 12 (9–18); 5.7 (5.3) TNK: 17 (12–22)
or median (IQR) TNK 0.25: 10 (6–15); ALT: 11 (8–16) ALT: 17 (12–22)
TNK 0.4: 9−5 to 17);
ALT 13 (5-17)
Permitted time window ≤3 h ≤6 h ≤4.5 h ≤4.5 h ≤4.5 h
Onset to treatment, mins, … 176 (48); 188 (44.5); TNK: 118 (79–180); TNK: 125 (102–156);
median (IQR) or mean (SD) TNK 0.1 3.1±0.9; TNK: 180 (156–215); ALT: 111 (80–174)* ALT: 134 (104–176)
TNK 0.25 3.0±0.7; ALT: 200 (160–220)
ALT 2.7±0.8
Atrial fibrillation … 28 (37.3%) 34 (35.4%) 119 (10.8%) …
Hypertension 89 (79.5) 47 (62.7%) 48 (50%) 482 (43.8%) …
Dyslipidemia 56 (50%) 37 (49.3%) 11 (11.5%) 126 (11.5%) …
Diabetes mellitus 21 (18.8%) 15 (20%) 14 (14.6%) 144 (13.1%) …
Current smoker 16 (14.2%) 15 (20%) 23 (24%) 346 (31.5%) …
Large vessel occlusion … 77% 47% … 100%
Endovascular Rx Prohibited Prohibited Prohibited Allowed Planned in all patients
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(used in 3%–4%)
sICH definition NINDS Study SITS-MOST SITS-MOST ECASS III SITS-MOST
ALT indicates alteplase; ATTEST, Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke; ECASS III, European-Australian Cooperative Acute Stroke
Study 3; EXTEND-IA, Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial; IQR, interquartile range; NIHSS, National Institutes of
Health Stroke Scale; NINDS, National Institute of Neurological Disorders and Stroke; sICH, symptomatic intracranial hemorrhage; SITS-MOST, Safe Implementation of
Thrombolysis in Stroke Monitoring Study; and TNK, tenecteplase.
*Data for time of onset to thrombolysis in the Nor-Test trial were available for 1035 patients (TNK, n=521; ALT, n=514).

crude mortality rates at 3 months were TNK 7.6% versus ALT
8.1%, risk difference 0% (95% CI, –3% to 2%; Figure VI in the
online-only Data Supplement). Though point estimates were
favorable, TNK CIs crossed the narrow noninferiority margins
that were set for both sICH and death. There was no evidence
of modification of treatment safety effects by TNK dose level
(Figures V and VI in the online-only Data Supplement).
For all comparisons, sensitivity analyses using a fixed
effects model yielded similar results to the analyses using
random-effects models.
Discussion
In this formal meta-analysis of head-to-head trials in AIS,
TNK demonstrated noninferiority to ALT. For the primary
efficacy end point, freedom from disability (mRS, 0–1) at 3
months, TNK in combined dose analysis exceeded each of the
assessed noninferiority margins, and each individual tested
dose exceeded the lead noninferiority margin. Similar findings
were present on the secondary efficacy end points of func-
tional independence (mRS, 0–2) and lower degree of disability
(shift analysis). Fewer trials contributed data to these analyses,
reducing power, but TNK still surpassed 2 of the 3 assessed
noninferiority margins, including the lead threshold. For the
safety end points of mortality at 3 months and sICH, point
estimates were also favorable for TNK, though CIs crossed
the tight noninferiority margins set for these outcomes.
Compared with the initial trials establishing ALT as a
proven stroke therapy, and compared with patients treated in
routine practice, the patients collectively enrolled in the ana-
lyzed TNK versus ALT trials were similar in age, sex, and
timing of therapy start, but had milder presenting stroke deficit
severity (NIHSS 7 in the current study versus NIHSS 12 in
the 2 pivotal National Institute of Neurological Disorders and
Stroke r-tPA trials and versus NIHSS 10 in US practice).10,11
This study’s findings of noninferiority are, therefore, more se-
cure for patients with milder (eg, NIHSS, 1–14) deficits than
patients with more severe (eg, NIHSS ≥15) deficits. However,
the one trial that focused solely on patients with large vessel
occlusions and severe deficits did provide strong signals of
noninferiority.12
The findings of this study are consistent with and substan-
tially add to prior meta-analyses of TNK versus ALT. Most
 Burgos and Saver   Tenecteplase is Noninferior to Alteplase   2159

Figure 1. Forest plot comparing TNK (tenecteplase) by dose subgroups vs ALT (alteplase), for the primary outcome: freedom from disability (mRS, 0–1).
Overall, the risk difference point estimate favored TNK over ALT: 4% (95% CI, −1% to 8%). The lower 95% CI bound of −1% fell within all of the assessed
noninferiority margins of −6.5%, −5%, and −1.3%, meeting all criteria for declaration of noninferiority. Dashed blue line indicates the lead −6.5% noninferior-
ity margin. ATTEST indicates Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke; and EXTEND-IA, Extending the Time for Thrombolysis
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in Emergency Neurological Deficits - Intra-Arterial.

prior systematic reviews included fewer trials, and all were
undertaken within a superiority rather than noninferiority
framework.13–16 The current study is the first to demonstrate
that, when the accumulated evidence is collated, TNK has
now met important criteria for noninferiority.
With regard to different doses of TNK, for the lead effi-
cacy outcome of freedom from disability (mRS, 0–1), there
was no evidence of heterogeneity of treatment effect across
the 3 studied TNK concentrations. However, power to de-
tect differences was constrained for the low, 0.1 mg/kg dose,
evaluated in the fewest patients, compared with the 0.25 mg/
kg and 0.4 mg/kg dose tiers. In addition, there was some ev-
idence of heterogeneity of treatment effect by TNK dose for
the secondary efficacy outcome of functional independence
(mRS, 0–2), suggesting that additional trial testing of different
dosages is warranted.
The optimal approach to performing meta-analyses to
evaluate noninferiority, rather than superiority, has not been
well-characterized in prior investigations and consensus state-
ments.5 The approach we have taken is a straightforward one:
first aggregating data across trials using standard study-level
meta-analytic techniques and then applying standard non-
inferiority testing, rather than superiority testing. This ge-
neral approach has been taken in another study, albeit in the
frame of sequential trial analysis rather than consolidated trial
analysis.17
In noninferiority analyses, selection of the noninferi-
ority margin to be applied can be challenging. Consensus
recommendations are that the noninferiority margin be the
smallest value that would be a clinically important effect.18
However, there often is a diversity of opinion in a field re-
garding what value demarcates the minimally clinically im-
portant difference of an outcome. The usual approach in
noninferiority analyses of employing only a single noninferi-
ority margin fails to take into account this spectrum of views.
Accordingly, for this analysis, we assessed 3 different nonin-
feriority margins of varying stringency, based on use in a prior
noninferiority trial or broad surveys of expert physicians. One
threshold that already employed in a peer-reviewed clinical
trial,6 was designated the lead, but the others were analyzed
as well to explore the robustness of the findings from the per-
spective of different stakeholder groups.7,8 That the lead effi-
cacy outcome surpassed all 3 assessed noninferiority margins
indicates a strong evidential basis for noninferiority claims.
The results of this study have direct implications for clin-
ical practice and treatment guidelines. TNK has been widely
recognized as offering highly desirable feasibility advantages
over ALT in the era of endovascular thrombectomy. Since it
can be administered as a one-time bolus dose, rather than as
an hour-long infusion, TNK can permit nonthrombectomy
hospitals to accelerate their door in—door out times for
patients needing intravenous thrombolysis followed by endo-
vascular thrombectomy, by obviating the need for less widely
available, nurse-staffed critical care ambulances for interfa-
cility transport. While ALT requires a strategy of drip and
ship, with the drip segment requiring 1 hour, TNK enables
 2160  Stroke  August 2019

Figure 2. Forest plot comparing TNK (tenecteplase) by dose subgroups vs ALT (alteplase), for the secondary efficacy outcome: functional independence
(mRS, 0–2). Overall, the risk difference point estimate favored TNK: 8% (95% CI, −4% to 20%). The lower 95% CI bound of −4% fell within the lead −6.5%
and intermediate −5% margins, meeting these noninferiority criteria, though not within the more stringent margin of −1.3%. Dashed blue line indicates the
lead −6.5% noninferiority margin. ATTEST indicates Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke; and EXTEND-IA, Extending the
Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial.
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a strategy of give and go, with the give segment requiring 1
minute. There is a potential drawback to TNK’s all-at-once
administration in that, with ALT, the longer infusion may be
stopped after only a partial dose if the patient exhibits signs
of potential hemorrhage; in addition, serum half-life of ALT
is shorter than TNK, allowing hemostasis to return more
quickly. However, these possible advantages of ALT in un-
common patients with early bleeding complications have not
been shown to importantly alter clinical outcome, and seem
unlikely to outweigh the substantial functional improve-
ments achieved with faster transfer to thrombectomy centers.
Accordingly, demonstration of noninferiority alone, even in
the absence of superiority, would make TNK a useful agent.
The prospect of that advantage led the most recent American
Heart/American Stroke Association AIS guideline to recog-
nize TNK as an alternative to ALT in patients with minor
neurological impairment and no major intracranial occlusion,
even in advance of any formal noninferiority analysis pro-
viding actual evidential support this recommendation.4 The
current noninferiority meta-analysis now provides a more ro-
bust foundation for recommendations regarding use of TNK
as an alternative to ALT.
This study has limitations. First, loss to follow-up is a
greater threat to analytic validity in noninferiority than su-
periority analyses. Some of the included trials did not have
complete outcome ascertainment at 3 months. However, rates
of loss to follow-up were quite low, mitigating this concern.
Second, power to explore differences in efficacy and safety
among different TNK dose tiers was limited, especially for the
lowest 0.1 mg/kg dose. Third, patients with severe presenting
deficits were under-represented in the analyzed trials. Further
head-to-head studies in patients with severe deficits are de-
sirable. Fourth, the analyzed trials primarily enrolled patients
within 4.5 hours of onset. While there is no clear pathophysi-
ologic reason to expect that the relative performance of TNK
and ALT would be different in patients selected for treatment
on the basis of imaging evidence of still salvageable tissue
>4.5 hours from last known well time, studies in late time win-
dows would be of value.
In conclusion, accumulated clinical trial data indicates in-
travenous TNK is noninferior to ALT in the treatment of AIS.
These findings provide formal support for recent guideline
recommendation to consider TNK an alternative to ALT in
patients with early cerebral ischemia. The available data are
not definitive, as the greatest weight of evidence is from a
trial that enrolled patients with mild deficits likely to have
good outcomes, diminishing study informativeness about
noninferiority, and because the most stringent noninferiority
margins were not met for secondary efficacy and safety out-
comes. Larger, definitive, noninferiority trials are desirable.
While awaiting them, use of TNK in lieu of ALT is reason-
able, especially in settings in which endovascular thrombec-
tomy would be expedited.
Acknowledgments
We thank Jeffrey Gornbein, PhD.
 Burgos and Saver   Tenecteplase is Noninferior to Alteplase   2161
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Disclosures
Dr Saver served as an unpaid consultant to Genentech advising on
the design and conduct of the PRISMS trial; neither the University
of California nor Dr Saver received any payments for this voluntary
service; received contracted hourly payments for services as a sci-
entific consultant advising on rigorous trial design and conduct to
Boehringer Ingelheim (prevention only); served as an unpaid site in-
vestigator in a multicenter trial sponsored by Boehringer Ingelheim
(nonlytic stroke prevention) for which the UC Regents received pay-
ments on the basis of clinical trial contracts for the number of subjects
enrolled. The other author reports no conflicts.
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