568135

research-article2015

VMJ0010.1177/1358863X14568135Vascular MedicineGeorge et al.

Original Article

A retrospective analysis of catheter-based

thrombolytic therapy for acute submassive
and massive pulmonary embolism

Vascular Medicine
2015, Vol. 20(2) 122130
The Author(s) 2015
Reprints and permissions:
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DOI: 10.1177/1358863X14568135
vmj.sagepub.com

Bennet George1, Eric L Wallace1, Richard Charnigo2,

Kelly E Wingerter3, Pavan Kapadia3, John C Gurley1 and
Susan S Smyth1

Abstract
Catheter-based thrombolysis (CBT) is emerging as an option for acute pulmonary embolism (PE). Although
prior studies have demonstrated improvement in right ventricular function, little data is available regarding
clinical patient outcomes. Our institution adopted CBT as an option for patients with submassive and massive PE
and we evaluated its effect on patient outcomes. Two hundred and twenty-one patients who presented to our
institution with submassive and massive PE were analyzed over three years by time period; 102 prior to the use of
CBT and 119 during the time CBT was performed. The primary outcome was in-hospital major adverse clinical
events (a composite of death, recurrent embolism, major bleeding, or stroke). Secondary outcomes were overall
and ICU length of stay and individual components of the composite outcome. Mean age was 56.316 years with
high rates of central PE (57.9%), RV dysfunction (37%), and myocardial necrosis (26%). Mean RV/LV ratio was 1.2.
Thirty-two patients were treated with CBT. The composite endpoint occurred more frequently in the CBT era vs
the pre-CBT era (21.0% vs 14.7%, p=0.23). After multivariate adjustment, CBT treatment demonstrated no effect
on major adverse clinical events (OR 0.84, CI 0.223.22, p=0.80). CBT era patients had an unadjusted 37% increase
in ICU days and 54% increase in total length of stay (p<0.001). Within the CBT era, CBT treatment resulted in
an adjusted 190% increase in overall length of stay (p<0.001). CBT did not demonstrate improvement in hospital
outcomes, despite adjustments of PE severity, and was associated with a significant increase in overall and ICU
length of stay.
Keywords
pulmonary embolism, submassive, catheter-based thrombolysis, fibrinolytics, outcomes

Introduction
Patient presentations for acute pulmonary embolism (PE)
vary widely. Traditional prognostic indices for hemodynamically stable patients with PE include evidence of right
ventricular (RV) dysfunction,1,2 presence of RV thrombus,1,3 elevated brain natriuretic peptide (BNP) levels,46
and elevated cardiac biomarkers.7,8 While most patients
receive anticoagulation as the cornerstone of medical therapy, systemic thrombolysis is recommended for patients
who are in shock or are hemodynamically unstable. One of
the major limitations of systemic thrombolysis is a high
incidence of bleeding.9 Limited small trials have evaluated
outcomes of thrombolytic therapy for acute PE with variable results, but pooled analysis demonstrates significantly
decreased composite endpoints of death and recurrent
thromboembolism.10
Patients with submassive PE represent a unique subset
of all PE patients. While systemic thrombolysis may not be

indicated, mortality remains high as they have evidence of

right ventricular (RV) dysfunction or myocardial necrosis
without features of overt shock.
In the last several years, variations in fibrinolytic dosing
have been evaluated in the intermediate risk population.
Low-dose tissue plasminogen activator (up to 50% of the

1Division

of Cardiovascular Medicine, Gill Heart Institute, University of

Kentucky, USA
2School of Public Health, University of Kentucky, USA
3Department of Internal Medicine, University of Kentucky, USA
Corresponding author:
Susan Smyth, Division of Cardiovascular Medicine, Gill Heart Institute,
University of Kentucky, 900 South Limestone Street, 326 Wethington
Building, Lexington, KY 405360200, USA.
Email: ssmyt2@email.uky.edu

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George et al.
full dose) in the MOPETT (Moderate Pulmonary Embolism
Treated with Thrombolysis) study demonstrated a large
reduction in clinical events without an increase in bleeding.11 However, enthusiasm has been tempered by the
PEITHO (Pulmonary Embolism Thrombolysis) study
which resulted in significant increases in major bleeding.12
Given that the potential benefits of fibrinolytic therapy may
be offset by concerns about adverse bleeding rates, further
large-scale studies are needed to define the role of thrombolysis further.
The use of catheter-based thrombolysis (CBT) has
emerged over recent years as a potential treatment option
for patients with submassive PE. Recently, randomized
studies have examined the use of this technology demonstrating improvements in RV function and dimension with
low rates of bleeding.13 However, these studies have not
evaluated clinical outcomes or compared treatment strategies of CBT to standard medical therapy in a real world
setting.13 Our institution recently adopted CBT as a treatment option for patients with submassive and massive PE,
and we sought to evaluate our experience.

Methods
Sample
The Institutional Review Board at the University Of
Kentucky approved this study. Patients included in the study
were selected using current procedural terminology codes for
PE as well as by reviewing the University of Kentucky
Catheterization Laboratory database. The sample consisted of
337 consecutive patients treated for acute PE between 1
March 2010 and 30 March 2013.
Individual computed tomography (CT) scans were
reviewed in order to confirm the presence of definite PE
and to define RV and LV (left ventricular) dimensions.
Patients with PE as identified by ventilation/perfusion
scanning were not included as part of the cohort. All pulmonary embolisms were classified further as central or segmental. Central pulmonary embolism was selected when
the thrombus was located in either the right, left, or main
pulmonary artery. In individuals with radiographic evidence of PE, the clinical investigators determined the
RV:LV ratio by individually reviewing chamber diameters.
Ventricular diameters were measured as the maximum distance from the interventricular septum to the endocardial
border perpendicular to the long axis of the heart.14 All
patients with a CT-determined RV:LV ratio 0.9 were
included in the study. Patients with RV:LV ratios of 0.7 to
0.9 were further investigated for other signs of RV dysfunction, as measured by echocardiogram or signs of myocardial necrosis. Massive and submassive groups were
determined according to American Heart Association
guidelines.15
A total of 114 patients were excluded as they did not
have radiographic evidence of having a PE or did not meet
criteria for submassive PE. In circumstances where a
patient had multiple admissions for a submassive PE, only
the most recent was included. The final sample consisted of
221 patients with acute submassive and massive PE. The

study design was a retrospective cohort analysis in which

outcomes were analyzed based on treatment strategy.
Consultation to the interventional service was left to the
discretion of the referring physician for consideration of
CBT therapy. Systemic thrombolysis was administered
with an institutional full dose alteplase infusion protocol
when clinically indicated.

Catheter-based thrombolysis procedure

Patients were administered therapeutic unfractionated or
low molecular weight heparin prior to the procedure.
Femoral venous access was obtained with ultrasound
guidance. In the majority of cases, when bilateral catheters were planned, two 6 French sheaths were placed in
the common femoral vein. The right and left pulmonary
arteries were then selectively engaged with diagnostic
catheters and next exchanged over a long wire for the
infusion catheters. An angled pigtail, Bernstein, or balloon tipped wedge catheter were most commonly used.
Catheterization laboratory standards were followed.16 The
procedure was considered a technical success if the
desired catheter was able to be delivered in stable position
with acceptable distal run off. Next, the alteplase infusion
was initiated at 1 mg/hour and ultrasound-assisted thrombolysis begun with the patient transferred to the intensive
care unit (ICU). The infusion was continued for 12 hours
in the case of bilateral catheters or 24 hours in unilateral
placement for a total dose of 24 mg. At the completion of
the alteplase infusion, pulmonary pressures were obtained
and the catheters were removed, including the access
sheaths regardless of clinical response. No additional systemic thrombolysis was administered. The patient was
continued on standard anticoagulation and patient disposition, including level of care, was left to the discretion of
the primary service.

Outcomes
Personnel, blinded to the study design, extracted pre-specified demographics and clinical data from our institutional
medical records. Data included patient demographics, medical comorbidities, baseline laboratory studies, baseline
vital signs, and management strategies. Repeat RV imaging
by echocardiography and CT were collected when available. Clinical events that had occurred by the time of discharge included death, length of stay, stroke or transient
ischemic attack, renal failure, urgent surgery, recurrent PE,
vascular complications, need for transfusion, and other
major bleeding events. For the purposes of our study, any
bleeding determined to have significantly altered patient
care was determined to be a major bleeding event (Bleeding
Academic Research Consortium [BARC] classification
25).17 Any events needing adjudication were determined
by two independent authors, who were blinded to the treatment strategy, with 100% agreement.
The primary outcome was a composite of major adverse
clinical events (MACE) including death, recurrent PE,
major bleeding, or stroke. Secondary outcomes focused on
in-hospital and ICU length of stay.

123

George et al.
full dose) in the MOPETT (Moderate Pulmonary Embolism
Treated with Thrombolysis) study demonstrated a large
reduction in clinical events without an increase in bleeding.11 However, enthusiasm has been tempered by the
PEITHO (Pulmonary Embolism Thrombolysis) study
which resulted in significant increases in major bleeding.12
Given that the potential benefits of fibrinolytic therapy may
be offset by concerns about adverse bleeding rates, further
large-scale studies are needed to define the role of thrombolysis further.
The use of catheter-based thrombolysis (CBT) has
emerged over recent years as a potential treatment option
for patients with submassive PE. Recently, randomized
studies have examined the use of this technology demonstrating improvements in RV function and dimension with
low rates of bleeding.13 However, these studies have not
evaluated clinical outcomes or compared treatment strategies of CBT to standard medical therapy in a real world
setting.13 Our institution recently adopted CBT as a treatment option for patients with submassive and massive PE,
and we sought to evaluate our experience.

Methods
Sample
The Institutional Review Board at the University Of
Kentucky approved this study. Patients included in the study
were selected using current procedural terminology codes for
PE as well as by reviewing the University of Kentucky
Catheterization Laboratory database. The sample consisted of
337 consecutive patients treated for acute PE between 1
March 2010 and 30 March 2013.
Individual computed tomography (CT) scans were
reviewed in order to confirm the presence of definite PE
and to define RV and LV (left ventricular) dimensions.
Patients with PE as identified by ventilation/perfusion
scanning were not included as part of the cohort. All pulmonary embolisms were classified further as central or segmental. Central pulmonary embolism was selected when
the thrombus was located in either the right, left, or main
pulmonary artery. In individuals with radiographic evidence of PE, the clinical investigators determined the
RV:LV ratio by individually reviewing chamber diameters.
Ventricular diameters were measured as the maximum distance from the interventricular septum to the endocardial
border perpendicular to the long axis of the heart.14 All
patients with a CT-determined RV:LV ratio 0.9 were
included in the study. Patients with RV:LV ratios of 0.7 to
0.9 were further investigated for other signs of RV dysfunction, as measured by echocardiogram or signs of myocardial necrosis. Massive and submassive groups were
determined according to American Heart Association
guidelines.15
A total of 114 patients were excluded as they did not
have radiographic evidence of having a PE or did not meet
criteria for submassive PE. In circumstances where a
patient had multiple admissions for a submassive PE, only
the most recent was included. The final sample consisted of
221 patients with acute submassive and massive PE. The

study design was a retrospective cohort analysis in which

outcomes were analyzed based on treatment strategy.
Consultation to the interventional service was left to the
discretion of the referring physician for consideration of
CBT therapy. Systemic thrombolysis was administered
with an institutional full dose alteplase infusion protocol
when clinically indicated.

Catheter-based thrombolysis procedure

Patients were administered therapeutic unfractionated or
low molecular weight heparin prior to the procedure.
Femoral venous access was obtained with ultrasound
guidance. In the majority of cases, when bilateral catheters were planned, two 6 French sheaths were placed in
the common femoral vein. The right and left pulmonary
arteries were then selectively engaged with diagnostic
catheters and next exchanged over a long wire for the
infusion catheters. An angled pigtail, Bernstein, or balloon tipped wedge catheter were most commonly used.
Catheterization laboratory standards were followed.16 The
procedure was considered a technical success if the
desired catheter was able to be delivered in stable position
with acceptable distal run off. Next, the alteplase infusion
was initiated at 1 mg/hour and ultrasound-assisted thrombolysis begun with the patient transferred to the intensive
care unit (ICU). The infusion was continued for 12 hours
in the case of bilateral catheters or 24 hours in unilateral
placement for a total dose of 24 mg. At the completion of
the alteplase infusion, pulmonary pressures were obtained
and the catheters were removed, including the access
sheaths regardless of clinical response. No additional systemic thrombolysis was administered. The patient was
continued on standard anticoagulation and patient disposition, including level of care, was left to the discretion of
the primary service.

Outcomes
Personnel, blinded to the study design, extracted pre-specified demographics and clinical data from our institutional
medical records. Data included patient demographics, medical comorbidities, baseline laboratory studies, baseline
vital signs, and management strategies. Repeat RV imaging
by echocardiography and CT were collected when available. Clinical events that had occurred by the time of discharge included death, length of stay, stroke or transient
ischemic attack, renal failure, urgent surgery, recurrent PE,
vascular complications, need for transfusion, and other
major bleeding events. For the purposes of our study, any
bleeding determined to have significantly altered patient
care was determined to be a major bleeding event (Bleeding
Academic Research Consortium [BARC] classification
25).17 Any events needing adjudication were determined
by two independent authors, who were blinded to the treatment strategy, with 100% agreement.
The primary outcome was a composite of major adverse
clinical events (MACE) including death, recurrent PE,
major bleeding, or stroke. Secondary outcomes focused on
in-hospital and ICU length of stay.

124

Vascular Medicine 20(2)

Table 1. Patient demographics.

Treatment era

Pre-CBT era

CBT era

p-value

Patients (n)
Age (mean years)
Male
Caucasian
Hypertension
Coronary artery disease
Congestive heart failure
Cerebrovascular accident
Diabetes mellitus
Chronic kidney disease
Chronic obstructive pulmonary disease
Previous pulmonary embolism
History of hypercoagulable state
Active malignancy
Body mass index
Recent surgery or prolonged immobility

102
5516
49.0%
82.4%
60.8%
15.7%
3.9%
9.8%
28.4%
5.9%
22.5%
9.8%
2.0%
27.5%
3310
29.4%

119
5716
52.1%
84.0%
55.5%
13.4%
4.2%
3.4%
15.1%
4.2%
20.2%
11.8%
9.2%
31.1%
3210
18.5%

0.25
0.65
0.74
0.42
0.64
0.92
0.05
0.02
0.57
0.67
0.64
0.02
0.55
0.62
0.06

CBT era
with medical
treatment

CBT era
with CBT
treatment

p-value

87
5916
49.4%
86.2%
56.3%
11.5%
3.4%
3.4%
12.6%
5.7%
18.4%
13.8%
8.0%
36.8%
329
18.4%

32
5216
59.4%
78.1%
53.1%
18.8%
6.3%
3.1%
21.9%
0.0%
25.0%
6.3%
12.5%
15.6%
3512
18.8%

0.05
0.34
0.29
0.76
0.30
0.50
0.93
0.21
0.21
0.43
0.26
0.46
0.03
0.14
0.96

CBT, catheter-based thrombolysis.

Significant differences shown in bold.

Statistical analysis
Outcomes were compared by treatment era, pre-CBT (from
March 2010 to September 2011) versus CBT (from
September 2011 to March 2013). In the CBT era, patients
were compared by treatment strategy (CBT versus medical
therapy). Dichotomous outcomes were summarized by percentages, with Fishers exact test used for comparisons.
Normally-distributed outcomes are summarized by means
and standard deviations with t-tests used for comparisons.
Numeric, but non-normally-distributed outcomes are summarized by medians and interquartile ranges with rank sum
tests used for comparisons.
Associations between MACE and individual patient
factors were estimated and tested for significance with
univariable logistic regression models. Patient factors
that were tested for potential association with future
events were selected based upon previously documented
associations with adverse outcomes including age, gender, diabetes, hypertension, chronic kidney disease,
known coronary artery disease, prior myocardial infarction, history of stroke, tobacco abuse, obesity (BMI>30),
and prior PE. The potential cardiac risk factors were
included in a multivariable logistic regression model if
they showed univariable associations with a p<0.20.
Results from logistic regression modeling were summarized by estimated odds ratios (OR) with corresponding
95% confidence intervals (CI).
The secondary outcomes of in-hospital and ICU length
of stay were also analyzed using univariable and multivariable modeling, similar to that described above, except
that linear regression replaced logistic regression, and
estimated regression coefficients (betas) replaced OR as
measures of effect. Because the secondary outcomes were
non-normally distributed, they were subjected to a transformation before linear regression modeling: add one, and

then take the natural logarithm; the offset of one was necessary because the logarithm of zero is undefined. Thus,
exponentiation of beta gives approximately the factor by
which the mean level of the (offset) outcome is multiplied
when the risk factor increases by one unit. A p-value less
than 0.05 was considered statistically significant. Version
9.3 of Statistical Analysis Software was used for data
analysis.

Results
The baseline demographics of the study population are displayed in Table 1. Overall, the two populations were comparable with only subtle differences including a higher
proportion of patients with diabetes being treated in the
pre-CBT era. Also, the CBT era saw more patients with a
history of hypercoagulable states and patients who had surgery within the last three months or a history of prolonged
immobilization.
Table 2 describes clinical characteristics at the time of
presentation, displayed by era and by treatment strategy in
the CBT era. Overall, the majority of patients were tachycardic (mean of 101 beats/minute) with low rates of shock:
3% overall (4% of patients in the pre-CBT compared to 2%
in the CBT era, p=NS) with minimal differences between
the groups. The most common enrollment criterion for submassive PE was RV/LV ratio>0.9, with average RV/LV
ratios being 1.11.2. A substantial percentage of patients
had evidence of RV dysfunction on echo and/or myocardial
necrosis, with no significant differences between the
groups. Notably, there were high rates of centrally located
PE in the population, with significantly more in the CBT
era population (66.4% versus 48.0%, p<0.01); no significant differences were noted between those in the CBT era
stratified by treatment (medical therapy versus CBT).

125

George et al.
Table 2. Clinical characteristics pre-treatment.
Treatment era

Pre-CBT era

CBT era

Patients (n)
Average heart rate (beats/minute)
Average systolic blood pressure (mmHg)
Centrally located pulmonary embolus
NSTEMI on admission*
RV dysfunction by echo*
Average RV/LV ratio by CT-chest

102
10022
12723
48.0%
27.5%
32.4%
1.20.4

119
10219
12722
66.4%
25.2%
40.3%
1.10.3

p-value

0.40
0.99
0.01
0.71
0.22
0.32

CBT era
with medical
treatment

CBT era
with CBT
treatment

p-value

87
10320
12622
70.1%
25.3%
40.2%
1.20.4

32
9916
12822
56.3%
25.0%
40.6%
1.10.3

0.39
0.69
0.16
0.97
0.97
0.27

CBT, catheter-based thrombolysis; NSTEMI, non-ST elevation myocardial infarction; RV, right ventricle; LV, left ventricle; CT, computed tomography.
Centrally located pulmonary embolus is defined as thrombus located in either the right, left, or main pulmonary artery.
*Cardiac biomarkers and echocardiograms were incompletely obtained. Percentages are displayed for the number of individuals with that specific
finding out of the total sample (n).

Table 3.Outcomes.
Treatment era

Pre-CBT era

CBT era

p-value

Number
Composite outcome
Major bleeding*
Any bleeding
Cerebrovascular accident
Intracranial hemorrhage
Length of stay
Required stay in intensive care unit (ICU)
Average length of ICU stay (days)
Required intubation
Required vasopressors
Recurrent pulmonary embolism
Death

102
14.7%
5.9%
11.8%
2.0%
1.0%
6.66.1
23.5%
1.13.1
13.7%
5.9%
3.9%
4.9%

119
21.0%
5.0%
12.6%
1.7%
0.8%
12.739.9
40.3%
2.35
34.5%
8.4%
10.9%
9.2%

0.23
0.78
0.85
0.88
0.91
0.12
0.01
0.03
<0.01
0.47
0.05
0.21

CBT era
with medical
treatment

CBT era
with CBT
treatment

p-value

87
23.0%
5.7%
14.9%
2.3%
1.1%
1028.1
100.0%
23.9
10.3%
8.0%
11.5%
10.3%

32
15.6%
3.1%
6.3%
0.0%
0.0%
20.361.3
41.4%
4.46.6
6.3%
9.4%
9.4%
6.3%

0.38
0.56
0.21
0.39
0.54
0.21
<0.01
0.02
0.49
0.82
0.74
0.49

CBT, catheter-based thrombolysis.

Significant differences shown in bold.
*Major bleeding was defined as per Bleeding Academic Research Consortium (BARC) classification.

In those receiving CBT therapy, the procedure was successfully completed in 100% of cases, without complications during catheter placement or infusion. Overall, the
composite endpoint of death, recurrent PE, major bleeding,
or stroke (MACE), occurred numerically, but not statically,
more frequently in the CBT era than the pre-CBT era
(21.0% versus 14.7%, p=0.23). Severe bleeding occurred
six times in each era with intracranial bleeding occurring
only once in each cohort. Minor access site bleeding
occurred in one patient late after CBT. Patients in the CBT
era were more likely to require ICU stay (40.3% versus
23.5%, p<0.01) or to require intubation (34.5% versus
13.7%, p<0.001) than those in the pre-CBT era. In addition,
there were numerically higher rates of death and recurrent
PE that were not statistically significant. Within the CBT
era alone, the composite outcome was higher in those
receiving CBT therapy versus medical therapy alone
(23.0% versus 15.6%, p=0.38). The remaining secondary
endpoints are seen in Table 3.
Univariate predictors for major adverse events are listed
in Table 4 with associated estimated odds ratio (OR). As

shown, prior PE was the only significant predictor of our

composite outcome amongst our total population with an
OR of 7.4 (CI 9.018.3, p<0.001) and demonstrated an
even stronger association within the CBT era alone (OR
23.8, CI 5.196.2, p<0.001). In addition, the RV/LV ratio
also predicted the composite outcome (OR 0.34, CI 0.12
0.95, p=0.04). Overall, treatment era had no effect on outcome (OR 1.54, CI 0.763.11, p=0.23). In multivariable
models, the only predictor of major in-hospital events, was
prior PE (OR 8.87, CI 3.3723.3, p<0.001). No treatment
effect was seen between the two eras (OR 1.26, CI 0.56
2.80, p=0.58, see Table 5). Within the CBT era, CBT therapy did not demonstrate a treatment benefit (OR 0.84, 95%
CI 0.223.22, p=0.80).
The effect of individual characteristics on ICU length of
stay (LOS) is displayed in Table 4. In the overall study population, chronic kidney disease, RV/LV ratio, evidence of
RV dysfunction, evidence of myonecrosis, and number of
submassive criteria were all significantly associated with
ICU length of stay. Patients in the CBT era spent on average 37% more time in the ICU than patients did prior to the

126

Vascular Medicine 20(2)

Table 4. Univariate predictors for major adverse events.

Univariable predictors of the composite outcome
Variable

Total population (n=221)

Est. OR

p-value

OR

0.16
0.37
0.74
0.74
0.55
0.52
0.44
<0.01
0.25
0.19
0.18
0.28
0.40
0.17
0.98
0.23

0.99
0.971.02
0.97
0.402.35
2.64
0.4216.72
Unable to estimate
2.65
0.868.20
0.72
0.192.71
0.94
0.108.78
23.83
5.9196.16
1.01
0.961.05
1.01
0.991.04
1.39
0.533.70
0.34
0.120.95
1.83
0.754.44
0.50
0.161.59
0.99
0.402.49
NA
0.83
0.302.30

0.70
0.95
0.30

0.09
0.63
0.95
<0.01
0.81
0.33
0.51
0.04
0.18
0.24
0.99

0.71

pvalue

OR

CI

pvalue

Univariable predictors of the ICU length of stay (log)

Age
0.01
0.010.01
Gender
0.13
0.100.35
Congestive heart failure
0.42
0.140.99
Prior cerebrovascular accident
0.03
0.490.43
Coronary artery disease
0.04
0.360.28
Diabetes mellitus
0.05
0.230.32
Chronic kidney disease
0.53
0.021.04
Prior pulmonary embolism
0.35
0.710.01
Body mass index
0.00
0.010.01
Presenting heart rate
0.00
0.010.01
Central pulmonary embolism
0.34
0.120.56
RV/LV ratio
0.59
0.90 0.28
RV dysfunction
0.58
0.370.80
NSTEMI
0.39
0.150.64
More than 1 criteria
0.38
0.160.61
CBT era
0.31
0.090.53
CBT therapy
NA

0.15
0.27
0.14
0.90
0.80
0.74
0.04
0.05
0.75
0.21
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01

0.01
0.23
1.05
0.33
0.02
0.40
0.60
0.36
0.01
0.01
0.34
0.79
0.70
0.46
0.42
NA
1.20

0.010.01
0.100.57
0.241.85
1.250.59
0.470.51
0.060.86
0.221.42
0.870.15
0.01 0.02
0.010.01
0.010.68
1.20 0.37
0.391.01
0.080.83
0.080.76

Univariable predictors of the overall length of stay (log)

Age
0.00
0.010.01
Gender
0.05
0.160.26
Congestive heart failure
0.92
0.401.44
Prior cerebrovascular accident
0.38
0.050.81
Coronary artery disease
0.10
0.400.20
Diabetes mellitus
0.13
0.130.38
Chronic kidney disease
0.24
0.250.72
Prior pulmonary embolism
0.31
0.650.03
Body mass index
0.01
0.010.02
Presenting heart rate
0.00
0.010.01
Central pulmonary embolism
0.21
0.010.42
RV/LV ratio
0.54
0.82 0.25
RV dysfunction
0.38
0.160.59
NSTEMI
0.08
0.160.32
More than 1 criteria
0.07
0.150.29
CBT era
0.17
0.040.38
CBT therapy
NA

0.75
0.65
<0.01
0.08
0.50
0.34
0.33
0.07
0.22
0.64
0.05
<0.01
<0.01
0.54
0.54
0.12

0.00
0.04
1.26
0.89
0.01
0.48
0.02
0.24
0.01
0.00
0.11
0.58
0.51
0.03
0.14
NA
0.54

0.010.01
0.360.27
0.502.00
0.031.75
0.460.47
0.050.91
0.750.81
0.730.24
0.010.02
0.010.01
0.220.44
0.98 0.18
0.210.82
0.390.33
0.180.47

Age
Gender
Congestive heart failure
Prior cerebrovascular accident
Coronary artery disease
Diabetes mellitus
Chronic kidney disease
Prior pulmonary embolism
Body mass index
Presenting heart rate
Central pulmonary embolism
RV/LV ratio+
RV dysfunction
NSTEMI
More than 1 criteria
CBT era
CBT therapy
Variable

0.99
0.73
1.31
1.25
1.32
0.75
0.44
7.44
1.02
1.01
1.64
0.61
1.35
0.54
1.01
1.54
NA
Est. beta OR

CI

CBT era (n=119)

0.961.01
0.371.46
0.266.55
0.334.72
0.533.32
0.311.82
0.063.53
3.0318.29
0.991.06
0.991.03
0.803.33
0.251.49
0.672.71
0.231.30
0.492.07
0.763.11
CI

CI

0.901.51

0.200.88

p-value

0.34
0.16
0.01
0.48
0.94
0.09
0.15
0.17
0.42
0.11
0.06
<0.01
<0.01
0.02
0.02

<0.01

0.98
0.79
<0.01
0.04
0.98
0.03
0.95
0.32
0.49
0.40
0.51
<0.01
<0.01
0.88
0.39

<0.01

CBT, catheter-based thrombolysis; OR, odds ratio; CI, confidence interval; RV, right ventricle; LV, left ventricle; NSTEMI, non-ST elevation myocardial
infarction; ICU, intensive care unit.
RV/LV ratio utilized was dichotomous with a cutoff of 0.9.
Significant differences shown in bold.

127

George et al.
Table 5. Multivariable predictors.
Multivariable predictors of the composite outcome
Variable

Total population (n=221)

Est. OR

95% CI

CBT era (n=119)

p-value

Variable

Est. OR

CAD
Prior Pulmonary
embolism
Presenting heart
rate
Central pulmonary
embolism
RV/LV ratio
RV dysfunction
CBT therapy

4.70
34.64

Variable

OR

Age
Prior pulmonary
embolism
Presenting heart rate

0.98
8.87

0.971.01
3.3723.34

0.13
<0.01

1.01

0.991.03

0.48

Central pulmonary
embolism
RV/LV ratio
RV dysfunction
CBT era

1.98

0.834.72

0.12

0.48
1.00
1.26

0.171.38
0.432.33
0.562.80

0.17
1.00
0.58

Variable

Est. beta OR

CI

pvalue

Multivariable predictors of the ICU length of stay (log)

Age
0.00
0.0040.009
CHF
0.34
0.2180.892
CKD
0.51
0.00991.0086
Presenting heart rate
0.00
0.00470.0056
Central pulmonary
embolism
RV/LV ratio
RV dysfunction
NSTEMI
CBT era

0.46
0.23
0.05
0.86

0.25

0.0250.482

0.03

0.46
0.37
0.17
0.19

0.78 0.131
0.120.62
0.080.427
0.0270.411

<0.01
< 0.01
0.18
0.09

Multivariable predictors of overall length of stay (log)

CHF
0.80
0.231.31
<0.01
CVA
0.31
0.100.72
0.14
Central pulmonary
0.18
0.030.39
0.09
embolism
RV/LV ratio
0.42
0.72 0.12
<0.01
RV dysfunction
0.21
0.020.43
0.07
CBT era
0.11
0.100.31
0.30

Diabetes
CHF
CKD
Presenting heart
rate
Central pulmonary
embolism
RV/LV ratio
RV dysfunction
NSTEMI
CBT therapy
CHF
CVA
Diabetes
RV/LV ratio
RV dysfunction
CBT therapy

95% CI
1.2118.32
7.42161.76

p-value
0.03
<0.01

1.01

0.981.04

0.57

1.64

0.162.34

0.47

0.36
1.85
0.84

0.081.50
0.4906.98
0.223.22

0.16
0.36
0.80

CI

pvalue

0.06
0.44
0.23
0.00

0.3030.419
0.2111.094
0.410.88
0.0040.009

0.75
0.18
0.48
0.78

0.02

0.260.31

0.88

0.72
0.13
0.19
1.08

1.09 0.35
0.180.44
0.120.50
0.771.40

<0.01
0.41
0.23
<0.01

0.86
0.59
0.23

0.131.59
0.231.41
0.190.65

0.02
0.16
0.27

0.38
0.21
0.43

0.780.02
0.120.54
0.080.77

0.06
0.22
0.01

CBT, catheter-based thrombolysis; OR, odds ratio; CI, confidence interval; CAD, coronary artery disease; RV, right ventricle; LV, left ventricle; ICU, intensive care unit; CHF, congestive heart failure; CKD, chronic kidney disease; NSTEMI, non-ST elevation myocardial infarction; CVA, cerebral vascular
accident.
Significant differences shown in bold.

introduction of CBT therapy. Within the CBT era alone,

those receiving CBT therapy spent, on average, over 200%
more time in the ICU. The (offset) ICU length of stay was
therefore increased, on average, by an estimated 190%
(95% CI, 116% to 305%, p<0.001) with CBT therapy in the
CBT era, after adjusting for other model variables. The
remaining multivariable predictors are shown in logarithmic scale in Table 5.
Analysis of the overall length of stay demonstrated
that congestive heart failure, increasing RV/LV ratios,
and evidence of RV dysfunction was associated in univariable modes with increased LOS, while the era was
not. After adjusting for model variables, only CHF and
RV/LV ratios remained significant. Within the CBT era,
CBT therapy was independently associated with prolonged hospitalization, requiring on average 53.7% (95%
CI, 8.3% to 115.9%, p<0.001) more time in the hospital

than for standard medical therapy, after adjustment for

medical co-morbidities. Table 5 displays the remaining
multivariable results.

Discussion
Patients with acute PE span a wide spectrum of clinical outcomes. Risk stratification of this population is important
and can impact treatment decisions. Patients are considered
low risk if they are hemodynamically stable, are without
evidence of RV dysfunction, and have normal cardiac biomarkers. The mortality rates for such low-risk patients
receiving standard therapy is around 3%.18 However, over a
third of normotensive patients with acute PE may have evidence of RV dysfunction or myocardial necrosis, placing
them at higher risk for in-hospital death or clinical deterioration with mortality rates as high as 40%.19,20

128
To date, the cornerstone of therapy for PE remains anticoagulation alone, even in patients with submassive PE.
Thrombolytic therapy is a treatment option for patients
with high-risk features, but patients with submassive PE
who would benefit from systemic thrombolysis are poorly
described.15,21 Compared with anticoagulation therapy
alone, systemic thrombolysis has not been demonstrated to
reduce mortality or recurrence of PE. In fact, data supports
the notion that major bleeding is increased, including
intracranial hemorrhage, thereby offsetting any potential
benefit.22 To date, this data has limited the expansion of
systemic thrombolysis therapy beyond the highest risk
patients.23 By instituting lower doses and targeting the
thrombolysis therapy to the pulmonary bed, CBT has the
potential to offset the previously noted bleeding complications and provide clinical benefit. Of note, the efficacy of
low-dose thrombolysis, which exhibits similar efficacy as
higher-dose thrombolytics, has not been directly compared
to a CBT strategy.24
One key consideration in the adoption of new technologies is demonstration of their overall safety and ease of
adoption. In general, placement of pulmonary infusion
catheters is not technically challenging. Several recent trials have demonstrated high procedural success rates and
appear to be associated with low rates of adverse events
(ULTIMA and SEATTLEII).13,25 Similar to these early
reports, we demonstrated high procedural success rates
(100%) without any immediate complications. In our
cohort, we evaluated in-hospital safety outcomes including
major bleeding, and no differences were noted between the
two treatment eras. A numerically higher, but not statistically significant, difference in bleeding was noted in those
receiving CBT therapy in the CBT era versus anticoagulation alone (5.7% versus 3.1%).
The overall effectiveness of CBT therapy is still not
well understood with early data demonstrating improvement surrogate outcomes such as RV function. In the
ULTIMA trial, intermediate-risk patients with PE, randomized to receive ultrasound-accelerated thrombolysis,
had significant improvement of RV dilation with RV/LV
ratios improving by 0.30 versus 0.03 (p<0.001) when
treated with heparin alone within the first 48 hours.
Improvement was also seen in RV function, and estimated
pulmonary artery pressures.13 Reassuringly, these results
were durable, sustaining these improved RV/LV ratios at
90 days. However, a catch up was noted in those receiving
heparin alone (RV/LV improvement from initial diagnosis
0.35 versus 0.24 in those treated with CBT versus heparin
respectively, p=0.07). Furthermore, the SEATTLEII trial,
which was a single-arm study evaluating the effectiveness
of CBT therapy, also showed a RV/LV ratio improvement
of 0.42 at 48 hours. However, no long term data is available at this time.25 In our study, follow-up echocardiogram
and CT scan rates were inadequate for formal analysis of
the RV function.
Despite the emerging data focused on surrogate outcomes, there are no studies evaluating whether initiation of
CBT for intermediate- to high-risk PE can improve patient
clinical outcomes. In our study, we selected a population
that consisted entirely of submassive or massive PE patients

Vascular Medicine 20(2)

and evaluated the outcomes of these patients in an era when
advanced treatments with catheter-based ultrasound therapies were available. Patients with submassive PE represented 42.1% of our institutional acute PE population. In
our sample, we did not demonstrate a significant short-term
improvement in our composite outcome when CBT was
introduced as a treatment modality for our high risk population. In fact, our composite outcome occurred numerically
more frequently in those in the CBT era than those prior to
CBT initiation. However, clinical differences existed
between the two eras, notably the presence of centrally
located PE, which could affect event rates. Therefore, in
multivariable models, we adjusted for clinical markers of
PE severity and known predictors of adverse events. After
adjustment, the increased rates of adverse events were
minimized and outcomes were nearly neutral (OR 1.25,
p=0.58). To assess these findings further, a separate analysis
was performed on those within the CBT era only, evaluating
the effect of CBT compared to medical therapy alone. After
adjusting for RV function, dilation, heart rate on presentation, and central PE, CBT therapy still was not associated
with a difference in patient outcomes (OR 0.84, p=0.80).
Clinical benefits beyond major adverse events may also
be seen with CBT therapy, including differences in overall
LOS and ICU LOS. The effect of CBT therapy on LOS has
not been compared in previous CBT studies. Despite a theoretical reduction in PE burden, and therefore quicker
improvement in hemodynamics with potential shorter critical care time, ICU LOS was actually longer in the CBT
group. In fact, on average, patients spent nearly triple the
time in the ICU when receiving CBT therapy. This association remained significant after adjustment for baseline
demographics and PE severity (OR 2.9, 95% CI, 0.16 to
4.05, p<0.001). There are significant limitations to this
data, as ICU LOS was largely driven by our institutional
CBT protocol. For example, patients receiving CBT therapy were routinely admitted to the ICU for post-procedural
monitoring with central access in place while fibrinolysis
was administered. While this only necessitated 1224
hours, we can conclude, however, that any benefit on ICU
LOS was far less than the time necessary to complete the
CBT therapy. Given the inherent limitations of an ICU LOS
endpoint, we further evaluated for any potential benefits on
overall LOS. Similarly, CBT therapy increased our hospital
LOS on average by over 50%, even after adjustment for
other patient variables.
Our study has several limitations worth discussing.
Firstly, our study was conducted at a single center where
there is no dedicated service for PE management. Therefore,
not all patients in the CBT era were considered for CBT
therapy or selected in a consistent manner across the institution. Secondly, confounders will always exist in patient
treatment decisions which cannot be adjusted for retrospectively despite our best attempts to collect all data pertinent
to PE severity. This specifically includes the subtle clinical
differences that may exist between patients with high-risk
submassive or massive PE in whom full-dose thrombolytics
may have prohibitively excess risk. We attempted to mitigate this bias by evaluating patient outcomes both during
and prior to our institutional availability of CBT therapy.

George et al.
Thirdly, our sample had a relatively small proportion of
patients undergoing CBT therapy. This limited our ability to
assess subgroups of patients in whom CBT may potentially
improve in-hospital outcomes. However, the study still
remains the first to analyze this unique group by clinicallydriven outcomes. Lastly, long-term clinical outcomes were
not assessed in this analysis. It is possible that the benefits of
CBT therapy extend beyond the immediate hospitalization.
Going forward, this unique population warrants further
investigation into new technologies to help improve both
acute and long-term outcomes. CBT therapy is one such
direction that needs to be investigated further, but the
rather rapid adoption of such innovative therapy is concerning given the lack of clinical outcomes data. In fact, a
large clinical study evaluating the effect of CBT therapy in
deep venous thrombosis confirmed our findings, demonstrating no improvement in major outcomes with increased
rates of adverse events and LOS.26 Together, these observational findings highlight the need for a large trial focused
on clinical outcomes, not just surrogate endpoints, to move
the approach of acute PE forward with the help of emerging technologies.

Conclusion
Our study found that the introduction of catheter based therapy for acute submassive and massive PE at our institution
was safe, but did not demonstrate appreciable improvements
in in-hospital outcomes. In addition, CBT therapy was associated with increased ICU and overall length of stay.
Declaration of conflicting interest
The authors declare that there is no conflict of interest.

Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.

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