693102

research-article2017
VMJ0010.1177/1358863X17693102Vascular MedicineCarroll et al.

Original Article

Vascular Medicine

Ultrasound-facilitated, catheter-directed, 1­–7

© The Author(s) 2017
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DOI: 10.1177/1358863X17693102
https://doi.org/10.1177/1358863X17693102
with pulmonary embolism: A SEATTLE journals.sagepub.com/home/vmj

II sub-analysis

Brett J Carroll1, Samuel Z Goldhaber2, Ping-Yu Liu3

and Gregory Piazza2

Abstract
Elderly patients with acute pulmonary embolism (PE) have higher mortality than non-elderly patients, but receive
systemic fibrinolysis less frequently. In this sub-analysis of the SEATTLE II trial, we evaluated the efficacy and safety of
ultrasound-facilitated, catheter-directed, low-dose fibrinolysis in elderly patients with submassive and massive PE. We
compared patients ⩾65 years old with those <65 years old. Eligible patients had proximal PE and a right ventricular-
to-left ventricular (RV/LV) diameter ratio ⩾0.9 on chest computed tomography (CT). The primary efficacy outcome
was the change in chest CT-measured RV/LV diameter ratio at 48 hours after procedure initiation. The primary safety
outcome was major bleeding within 72 hours. Sixty-two patients were ⩾65 years of age and 88 were <65 years of age.
The RV/LV diameter ratio decreased in both groups 48 hours post-procedure, with a mean change of −0.47 in those
⩾65 and −0.39 in those <65 years old, with no difference between groups (p = 0.31). Major bleeding occurred in nine
(15%) of those ⩾65 and in six (7%) of those <65 years old (p = 0.17). Ultrasound-facilitated, catheter-directed, low-dose
fibrinolysis resulted in a similar reduction in RV/LV diameter ratio in elderly patients with massive and submassive PE
compared with non-elderly patients.

Keywords
aging, fibrinolysis, pulmonary embolism, thrombolytic therapy

Introduction
Pulmonary embolism (PE) is the third most common cause
of cardiovascular death in the United States, and its inci-
dence is increasing.1–4 PE occurs more frequently with
advancing age and results in higher mortality in the elderly
population.1,5 Systemic fibrinolysis decreases mortality and
prevents cardiovascular collapse, particularly in the highest
risk patients.6–8 Despite these findings, its utilization
remains low, particularly among elderly patients, owing to
concerns of increased bleeding, specifically intracranial
hemorrhage (ICH).1,9,10 The overall risk of bleeding
increases incrementally by 4% with each year of age.10 The
risk of ICH appears to be significantly greater in the elderly
population >75 years old, which has been considered a rela-
tive contraindication for the administration of systemic
fibrinolysis in recent guidelines.6,11,12
Ultrasound-facilitated, catheter-directed, low-dose
venous administration. The SEATTLE II trial examined the
safety and efficacy for reversal of RV dysfunction of ultra-
sound-facilitated, catheter-directed, low-dose fibrinolysis
in 150 patients with massive or submassive PE.13 The trial
showed decreased right ventricular (RV) size, computed
tomography (CT) angiographic thrombus burden, and pul-
monary artery systolic pressure 48 hours post-procedure.
The rate of major bleeding (10%) was lower than historical
rates for full-dose systemic fibrinolysis, and no ICH was
1Division of Cardiology, Department of Medicine, Beth Israel Deaconess
Medical Center, Boston, MA, USA
2Cardiology Division, Department of Medicine, Brigham and Women’s
Hospital, Boston, MA, USA
3Fred Hutchinson Cancer Center, Seattle, WA, USA

fibrinolysis may improve right ventricular function with a

reduced bleeding risk. The recommended dose of tissue-
plasminogen activator (t-PA) is 24 mg, compared with the
United States Food and Drug Administration (FDA)-
approved dosing regimen of 100 mg of t-PA for peripheral
Corresponding author:
Brett Carroll, Division of Cardiology, Department of Medicine, Beth
Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA
02215-5491, USA.
Email: bcarrol2@bidmc.harvard.edu
2 Vascular Medicine
observed.13,14 Similarly, the ULTIMA trial in submassive
PE patients showed improvement in RV function with
ultrasound-facilitated, catheter-directed, low-dose fibrinol-
ysis compared to anticoagulation alone, with no major
bleeding events.15
Given the increased mortality rate of PE and the risks of
complications from systemic fibrinolysis in the elderly
population, we evaluated the safety and efficacy of ultra-
sound-facilitated, catheter-directed, low-dose fibrinolysis
in this high-risk population by performing a subgroup anal-
ysis of the SEATTLE II trial.
Methods
Study design
The methodology of SEATTLE II has been previously
described in detail,13 but, in brief, 159 hospitalized patients
with acute massive or submassive PE were screened and
150 were prospectively enrolled between June 2012 and
February 2013 at 22 sites across the United States.
Patients were eligible if they had a massive or submas-
sive PE with a filling defect in at least one main or lobar
pulmonary artery and an right ventricular-to-left ventricu-
lar (RV/LV) diameter ratio of ⩾0.9 on contrast-enhanced
chest CT. The EkoSonic Endovascular System (EKOS,
Bothell, WA, USA) catheters were placed into the pulmo-
nary arteries via the common femoral or internal jugular
vein. Baseline right heart pressures were measured prior to
delivery of fibrinolytic therapy or activation of ultrasound.
The fixed-dose regimen of t-PA (Genentech, South San
Francisco, CA, USA) was 24 mg at 1 mg/hour for both
unilateral and bilateral PEs. For patients with predomi-
nantly unilateral PE, a single catheter was placed with
infusion of t-PA over 24 hours. For patients with bilateral
PE, two catheters were placed with infusion of t-PA over
12 hours in each catheter. After completion of the proce-
dure, but prior to catheter removal, right heart pressures
were measured. Follow-up contrast-enhanced chest CT
and transthoracic echocardiography were performed
within 48 ± 6 hours after initiation of the procedure. The
changes in the right ventricular (RV)-to-left ventricular
(LV) diameter ratio and modified Miller angiographic
obstruction index score were assessed by the chest CT per-
formed at baseline and at 48 hours.16 Echocardiography
was performed to estimate pulmonary artery systolic pres-
sure at 48 ± 6 hours. Bleeding complications were assessed
for 72 hours after the procedure. Overall, 149 of 150
patients completed the required clinical follow up.
Outcomes
The primary efficacy outcome was the core laboratory-
measured change in RV/LV diameter ratio from baseline
and at 48 hours post-initiation of the procedure.17 Secondary
efficacy outcomes included the change in pulmonary artery
systolic pressure before the procedure, measured at the con-
clusion of the procedure, and estimated by transthoracic
echocardiography at 48 hours. An additional secondary out-
come was the change in core laboratory-measured modified
Miller score for angiographic obstruction evaluated by con-
trast-enhanced chest CT and follow-up scan performed at
48 hours.
The primary safety outcome was major bleeding within
72 hours of initiation of the procedure. Bleeding events
were classified by the Global Utilization of Streptokinase
and Tissue Plasminogen Activator for Occluded Coronary
Arteries (GUSTO) bleeding criteria.18 All safety outcomes
were adjudicated by a designated independent Study Safety
Monitor.
Statistical analysis
Sub-analysis was performed comparing patients <65 and
⩾65 years of age. Continuous variables were generally
compared between the two groups using a two-sample
t-test. The Fisher’s exact test was used for binary data. All
reported p-values were two-sided and a p-value <0.05 was
considered statistically significant. All statistical analyses
were performed using SAS statistical software version 9.2
(SAS Institute Inc., Cary, NC, USA).
Results
Baseline demographics and clinical
characteristics
The elderly patient cohort comprised 62 patients who
were ⩾65 years of age with a mean age of 74 years com-
pared with 88 patients <65 years of age who had a mean
age of 48 years. Those ⩾65 years old had higher rates of
comorbidities, including hypercholesterolemia, hyperten-
sion, diabetes, atherosclerotic disease, hepatic or renal
insufficiency, and chronic obstructive pulmonary disease
(Table 1). Those <65 years old had significantly greater
weight and body mass index. There were no differences in
rates of prior transient ischemic attack or stroke, cancer,
or prior PE or deep vein thrombosis. There were similar
rates of risk factors for development of PE, including
immobility, family history of venous thromboembolism
(VTE), or recent trauma or surgery.
There were no differences in PE symptoms, duration, or
severity upon presentation (Table 2). There was a higher
rate of antiplatelet use prior to the procedure in the elderly
group. Procedural characteristics were similar with respect
to the total dose of t-PA received, rate of successful place-
ment of the device, and number of catheters placed per
patient (Table 3).
Efficacy outcomes
A follow-up CT scan was performed within the 48 ± 6-hour
window in 42 (68%) of those ⩾65 years old and in 74
(84%) of those <65 years old (p = 0.03) (Table 4). The
mean baseline RV/LV diameter ratio on CT was similar
between the two groups (1.58 in those ⩾65 vs 1.53 in those
<65, p = 0.48) (Figure 1A). The mean RV/LV diameter ratio
at 48 hours decreased in both age groups (mean absolute
change of −0.47 in those ⩾65 (p < 0.0001) and −0.39 in
those <65 (p < 0.0001)). The degree of decrease in RV/LV
Carroll et al. 3

Table 1.  Baseline demographics and clinical characteristics.

Age ⩾ 65 Age < 65 p-value

n=62 n=88
Age, years 74.1 ± 6.6 48.3 ± 11.7  
Weight, lbs (kg) 219.2 ± 58.4 (99.4 ± 26.5) 242.3 ± 65.2 (109.9 ± 29.6) 0.02
Body mass index, kg/m2 33.9 ± 8.3 36.8 ± 9.5 0.05
Female 32 (52) 45 (51) 1.00
Ethnicity/race
 Caucasian 52 (84) 67 (76)  
  African American 5 (8) 17 (19)  
  Hispanic or Latino 5 (8) 4 (5) 0.31a
Hypercholesterolemia 41 (66) 28 (32) 0.0001
Coronary artery disease 8 (13) 2 (2) 0.02
Hepatic or renal insufficiency 11 (18) 2 (2) 0.002
TIA or stroke 6 (10) 3 (3) 0.16
Active cancer 4 (7) 2 (2) 0.23
History of cancer 17 (27) 14 (16) 0.10
Heart failure 5 (8) 2 (2) 0.13
Diabetes 27 (44) 15 (17) 0.0005
Hypertension 55 (89) 39 (44) <0.0001
Atherosclerotic cardiovascular disease 14 (23) 4 (5) 0.002
Tobacco use 10 (16) 17 (20) 0.67
Obesity 31 (51) 51 (59) 0.40
Chronic obstructive pulmonary disease 10 (16) 3 (3) 0.01
Immobility within 30 days of PE 20 (32) 25 (29) 0.72
Chronic inflammatory disorders 3 (5) 5 (6) 1.00
Family history of venous thromboembolism 10 (16) 21 (24) 0.31
Acute infectious illness within past 30 days 5 (8) 15 (17) 0.14
Hormonal contraceptive or replacement therapy 1 (2) 15 (17) 0.002
Recent major surgery 2 (3) 4 (5) 1.00
Recent trauma 5 (8) 3 (3) 0.28
Recent gastrointestinal or genitourinary bleeding 3 (5) 3 (3) 0.69
History of PE 4 (6) 12 (14) 0.19
History of deep venous thrombosis 15 (24) 18 (20) 0.69

Values are mean ± SD or n (%).

aCaucasian vs non-Caucasian.

PE, pulmonary embolism; TIA, transient ischemic attack.

Table 2.  Characteristics of pulmonary embolism and initial anticoagulation.

Age ⩾ 65 Age < 65 p-value

n=62 n=88
Any symptoms of PE 62 (100) 88 (100) 1.0
Duration of symptoms, days  
  ⩽14 62 (100) 87 (99)  
 >14 0 (0) 1 (1) 1.0
PE subtype  
 Submassive 50 (81) 69 (78)  
 Massive 12 (19) 19 (22) 0.84
Pre-procedure anticoagulationa 55 (89) 71 (81) 0.26
 Aspirin 28 (45) 19 (22) 0.003
 Clopidogrel 2 (3) 3 (3) 1.0
  Intravenous unfractionated heparin 36 (58) 43 (49) 0.32
 Enoxaparin 22 (35) 32 (36) 1.0
 Warfarin 5 (8) 11 (13) 0.43
 Other 4 (6) 3 (3) 0.45
 None 7 (11) 17 (19) 0.26

Values are n (%).

aPatients could have received more than one antiplatelet/anticoagulant.

PE, pulmonary embolism.

4 Vascular Medicine

Table 3.  Procedural characteristics.

Age ⩾ 65 Age < 65 p-value

n=62 n=88
Total dose of t-PA, mga 23.7 ± 3.0 23.7 ± 2.8 0.95
Successful device placementb 116 (98) 162 (97)  
Access sites 0.56c
  Right femoral vein 71 (61) 106 (65)  
  Left femoral vein 30 (26) 31 (19)  
  Right internal jugular vein 13 (11) 18 (11)  
 Other 2 (2) 7 (4)  
No. of devices per patient 1.0
 0 0 (0) 1 (1)  
 1 8 (13) 12 (14)  
 2 54 (87) 75 (86)  
Completed infusion of t-PA 112 (97) 160 (99) 0.39c

Values are mean ± SD or n (%).

aN = 150 patients (1 patient <65 died before devices could be placed).
bDevices attempted = 118 in those ⩾65 years and 167 in those <65.
cP-values by mixed model repeated measures (MMRM) analysis to account for potential correlations between two devices placed in the same patient.

t-PA, tissue-plasminogen activator.

Table 4.  Efficacy outcomes.

Age ⩾ 65 Age < 65 p-value

(n) (n)
RV/LV diameter ratio
 Baseline 1.58 ± 0.41 (48) 1.53 ± 0.38 (75) 0.48
  48 hours after procedure 1.13 ± 0.19 (42) 1.13 ± 0.23 (74) 0.84
  Change 48 hours after procedure −0.47 ± 0.42 (42)a −0.39 ± 0.33 (73)a 0.31
Modified Miller score
 Baseline 23.0 ± 5.3 (48) 22.2 ± 6.0 (75) 0.40
  48 hours after procedure 15.9 ± 5.7 (43) 15.7 ± 6.0 (74) 0.85
  Change 48 hours after procedure −7.4 ± 6.6 (43)a −6.2 ± 6.2 (73)a 0.31
PA systolic pressure, mmHg
 Baseline 52.0 ± 13.0 (62) 51.0 ± 17.9 (88) 0.70
  At procedure completion 39.2 ± 11.6 (60) 36.3 ± 12.0 (87) 0.15
  Absolute difference −13.1 ± 13.0 (60)b −14.6 ± 16.3 (87)b 0.54
  48 hours after procedure 39.8 ± 14.0 (43) 34.6 ± 15.3 (55) 0.08
  Absolute difference −11.0 ± 13.6 (43)a −17.0 ± 16.4 (55)a 0.053

Values are mean ± SD (n).

aIn-group difference between baseline and 48 hours after procedure, p < 0.0001.
bIn-group difference between baseline and after procedure, p < 0.0001.

LV, left ventricular; PA, pulmonary artery; RV, right ventricular.

diameter ratio was similar between the two groups (p=0.31).
When also including patients with CT outside of the pre-
specified window (89% in those ⩾65 and 97% in those
<65, p = 0.09), the findings of similar improvement in
mean change in RV/LV diameter ratio between the two
groups persisted (−0.5 vs −0.41, p = 0.28). Modified Miller
scores were also similar at baseline (23 in those ⩾65 vs
22.2 in those <65, p = 0.40), with a decrease at 48 hours
within each group (mean change of −7.4 in those ⩾65 (p <
0.0001) and −6.2 in those <65 (p < 0.0001)), with no differ-
ence between groups (p = 0.31) (Figure 1B).
Pulmonary artery systolic pressures were similar
between the two groups at baseline (52.0 mmHg in those
⩾65 vs 51.0 mmHg in those <65 years old, p = 0.70)
(Figure 1C). Both groups had decreases in pulmonary pres-
sure at completion of the procedure compared with baseline
measurements, with no difference in mean change (−13.1
mmHg in those ⩾65 vs −14.6 mmHg in those <65, p =
0.54) or absolute value (39.2 mmHg in those ⩾65 vs 36.3
mmHg in those <65, p = 0.15) between groups. Forty-
three (69%) patients ⩾65 and 55 (63%) <65 had a tran-
sthoracic echocardiogram performed within the 48 ±
6-hour post-procedure window. The estimated average
pulmonary artery systolic pressure from echocardiogram
at 48 hours post-procedure was not significantly different
between the two groups (39.8 mmHg in those ⩾65 vs 34.6
mmHg in those <65, p = 0.08). Both groups had a decrease
in estimated pulmonary pressures on echocardiogram
compared to baseline (p < 0.0001 in both groups), with a
trend toward greater improvement in the younger group
(mean change of −11.0 mmHg in those ⩾65 vs −17.0
mmHg in those <65, p = 0.053). A small percentage of
Carroll et al. 5
Figure 1.  (A) Change in contrast-enhanced CT-determined
mean RV/LV diameter ratio from baseline to 48 ± 6 hours after
initiation of the ultrasound-facilitated, catheter-directed, low-
dose fibrinolytic procedure. (B) Change in contrast-enhanced
CT-determined mean modified Miller pulmonary angiographic
obstruction index score from baseline to 48 ± 6 hours after
initiation of ultrasound-facilitated, catheter-directed, low-dose
fibrinolytic procedure. (C) Change in invasively measured mean
systolic pulmonary artery pressure from baseline to completion
of the ultrasound-facilitated, catheter-directed, low-dose
fibrinolytic procedure and to 48 ± 6 hours after the procedure
estimated by transthoracic echocardiogram.
patients underwent transthoracic echocardiography out-
side of the 48 ± 6-hour window in both groups (10% vs
13%). When including all patients who underwent follow-
up echocardiography, there was a trend toward greater
improvement in pulmonary artery systolic pressure in the
younger cohort (−11.4 mmHg vs −17.3 mmHg, p = 0.05).
The elderly and non-elderly groups had a similar pro-
portion of patients with a massive PE (19% in those ⩾65
and 22% in those <65 years old). There were similar
improvements in the RV/LV ratio between groups in those
with massive PE (−0.42 in those ⩾65 and −0.53 in those
<65, p = 0.51) and submassive PE (−0.48 in those ⩾65 and
−0.35 in those <65, p = 0.13). There were also similar
improvements in the modified Miller Index ratio between
groups in those with massive PE (−11.0 in those ⩾65 and
−9.3 in those <65, p = 0.52) and submassive PE (−5.2 in
those ⩾65 and −6.6 in those <65, p = 0.30), along with a
decrease in PA pressure at 48 hours in massive PE (−10.7
mmHg in those ⩾65 and −13.3 mmHg in those <65, p =
0.71) and submassive PE (−11.1 mmHg in those ⩾65 and
−18.1 mmHg in those <65, p = 0.05).
Safety outcomes
Length of stay was similar between groups (9.5 days in
those ⩾65 vs 8.3 days in those <65 years old, p = 0.17)
(Table 5). One patient <65 years old died prior to the proce-
dure being completed. Both in-hospital mortality (1 in
those ⩾65 vs 2 in those <65, p = 1.0) and 30-day mortality
(2 in those ⩾65 vs 2 in those <65, p = 1.0) were similar
between groups. There were no significant differences in
adjudicated adverse events related to the device (2 in those
⩾65 vs 1 in those <65, p = 0.57) or t-PA (2 in those ⩾65 vs
0 in those <65, p = 0.17). Major bleeding occurred in nine
(15%) of those ⩾65 and in six (7%) <65 (p = 0.17). No
patient ⩾65 and one patient <65 experienced GUSTO-
defined severe bleeding. No patients in either group suf-
fered intracranial hemorrhage.
Discussion
We did not observe a significant difference in primary safety
or efficacy outcomes between elderly and non-elderly
patients undergoing ultrasound-facilitated, catheter-directed,
low-dose fibrinolysis for acute PE. We did observe similar
decreases in RV/LV ratio, pulmonary artery angiographic
obstruction, and pulmonary artery pressures over 48 hours in
those ⩾65 years old compared with those <65 years old. The
rate of major bleeding was similar in both groups but trended
toward more frequent bleeding in the elderly.
Utilization of thrombolysis to treat submassive and mas-
sive PE has been limited due to bleeding concerns.19 The
risk of bleeding with fibrinolysis, particularly of intracranial
hemorrhage, increases when treating elderly individuals.9,10
Factors that contribute to increased bleeding in elderly
patients who receive thrombolysis include higher rates of
hypertension,20 hepatic or renal insufficiency,21,22 diabe-
tes,22,23 antiplatelet utilization,24 and lower weight.25,26 We
observed a higher prescription of antiplatelet therapy before
the procedure in elderly patients. In the randomized-con-
trolled trial PEITHO, which compared full-dose systemic
fibrinolysis plus anticoagulation versus anticoagulation
alone in high-risk submassive PE patients, 2% who received
systemic fibrinolysis sustained an intracranial hemorrhage.6
All were ⩾65 years old. Increased major extracranial bleed-
ing was also seen in the elderly subgroup analysis of
PEITHO, with a rate of 11.1% in those >75 years old com-
pared with 4.1% in those ⩽75 years old.
6 Vascular Medicine

Table 5.  Safety outcomes.

Age ⩾ 65 Age < 65 p-value

n=62 n=88
Length of stay, days 9.5 ± 4.8 8.3 ± 5.1 0.17
In-hospital death 1 (2) 2 (2) 1.0
30-day mortalitya 2 (3) 2 (2) 1.0
Serious and severe adverse events potentially 2 (3) 1 (1) 0.57
related to device
Serious and severe adverse events potentially 2 (3) 0 (0) 0.17
related to t-PA
IVC filter placed 11 (18) 13 (15) 0.66
Major bleeding within 30 daysa 9 (15) 6 (7) 0.17
  GUSTO moderate 9 (15) 5 (6)  
  GUSTO severe 0 (0) 1 (1)  
Intracranial hemorrhagea 0 (0) 0 (0) 1.0

Values are mean ± SD or n (%).

aOne patient <65 years old lost to follow up.

GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; IVC, inferior vena cava; t-PA, tissue
plasminogen-activator.

In PEITHO, there was a decreased rate of death or
hemodynamic decompensation with systemic thrombolysis
in those ⩽75 years old, which was not observed in those
>75 years old. Our analysis showed similar efficacy with
comparable decreases in the RV/LV diameter ratio from
baseline to 48 hours across different age groups.
Ultrasound-facilitated, catheter-directed fibrinolysis,
with its low dose of t-PA of 24 mg compared with 100 mg
as the full systemic dose, may be an attractive option to
rapidly reduce RV pressure overload in the elderly popula-
tion. An ongoing clinical trial is testing lower t-PA dosing
regimens and shorter durations of therapy, which may fur-
ther improve safety and efficiency without compromising
efficacy (see NCT02396758).
Limitations and strengths
Although the elderly patient subgroup was compared with a
non-elderly group, there was no comparator group that
received an alternative treatment. Therefore, we cannot com-
ment on the efficacy or safety outcomes of this treatment
approach compared to alternatives such as anticoagulation
alone, systemic fibrinolysis, or catheter-directed fibrinoly-
sis without ultrasound-assistance. No data were collected
regarding follow up beyond 30 days, and clinical efficacy
outcomes were limited to mortality. The rate of comorbidi-
ties was higher in the elderly group, which might confound
outcomes. Fewer elderly patients had a follow-up CT scan
within the 48-hour window. Finally, sample size may have
limited the power of our analysis to detect differences in out-
comes between elderly and non-elderly patients, including
the comparison of outcomes in massive and submassive PE.
We report the largest prospective case series of elderly
patients to undergo ultrasound-facilitated, catheter-directed,
low-dose fibrinolysis for both submassive and massive PE.
We assessed three parameters for short-term improve-
ment in patients with PE, including decreased RV/LV ratio,
pulmonary artery systolic pressures, and anatomic extent of
thrombus. We also utilized a robust and inclusive assess-
ment of bleeding.
Conclusions
Ultrasound-facilitated, catheter-directed, low-dose fibrinol-
ysis improved RV function, reduced pulmonary artery angi-
ographic obstruction, and decreased pulmonary artery
systolic pressure in those ⩾65 years old without intracra-
nial hemorrhage. Ultrasound-facilitated, catheter-directed,
low-dose fibrinolysis appears to be a reasonable treatment
option for elderly patients with massive or submassive PE.
Declaration of conflicting interests
Dr Piazza receives research grant support from EKOS, a BTG
International Group company, Bristol-Myers Squibb, Daiichi-
Sankyo, and Janssen. Dr Liu receives consulting fees from EKOS,
a BTG International Group company. Dr Goldhaber receives
research grant support from EKOS, a BTG International Group
company, Bristol-Myers Squibb, Daiichi-Sankyo, and Janssen.
Funding
The authors disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: this study
was funded by a research grant from EKOS, a BTG International
group company. The sponsor had no role in data interpretation or
writing the manuscript. BJC, SZG, and GP had full access to the
data and had final responsibility for the decision to submit for pub-
lication. The sponsor of the trial was in possession of the database.
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