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Real-World Outcomes of EKOS Ultrasound-Enhanced Catheter-Directed Thrombolysis for Acute Limb Ischemia
Journal Pre-proof Real-World Outcomes of EKOS Ultrasound-Enhanced Catheter-Directed Thrombolysis for Acute Limb Ischemia Elizabeth L. George, Benjamin Colvard, Vy-Thuy Ho, Kara A. Rothenberg, Jason T. Lee, Jordan R. Stern PII:
S0890-5096(20)30003-0
DOI:
https://doi.org/10.1016/j.avsg.2019.12.026
Reference:
AVSG 4838
To appear in:
Annals of Vascular Surgery
Received Date: 15 November 2019 Revised Date:
30 December 2019
Accepted Date: 30 December 2019
Please cite this article as: George EL, Colvard B, Ho VT, Rothenberg KA, Lee JT, Stern JR, Real-World Outcomes of EKOS Ultrasound-Enhanced Catheter-Directed Thrombolysis for Acute Limb Ischemia, Annals of Vascular Surgery (2020), doi: https://doi.org/10.1016/j.avsg.2019.12.026. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
1
Real-World Outcomes of EKOS Ultrasound-Enhanced Catheter-Directed Thrombolysis
2
for Acute Limb Ischemia
3 4
Elizabeth L Georgea, Benjamin Colvarda, Vy-Thuy Hoa, Kara A Rothenbergb, Jason T Leea,
5
Jordan R Sterna
6 7
a
8
School of Medicine, Stanford, CA.
9
b
Department of Surgery, Division of Vascular & Endovascular Surgery. Stanford University
Department of Surgery, University of California San Francisco – East Bay. Oakland, CA.
10 11
Corresponding Author:
12
Jordan R. Stern, MD
13
Division of Vascular & Endovascular Surgery, Stanford University
14
300 Pasteur Drive, Alway M-121
15
Stanford, CA 94305
16
[email protected]
17 18
Keywords: ultrasound-enhanced catheter-directed thrombolysis, EKOS system, acute limb
19
ischemia
20
21
Abstract
22 23
Objectives: Ultrasound-enhanced catheter-directed thrombolysis (UET) using the EKOS device
24
for acute, peripheral arterial ischemia has been purported in clinical trials to accelerate the
25
fibrinolytic process in order to reduce treatment time and lytic dosage. We aim to describe
26
outcomes of UET in a real-world clinical setting.
27 28
Methods: We performed a retrospective review of all patients undergoing UET for acute limb
29
ischemia at a single institution. Data collected included patient demographics, procedural details,
30
and 30-day and 1-year outcomes. The primary endpoints for analysis were major adverse limb
31
events (MALE; reintervention and/or amputation) and mortality within 30-days and 1-year.
32
Secondary endpoints included technical success, use of adjunctive therapies, and postoperative
33
complications.
34 35
Results: 32 patients (mean age 67.4 ± 14.9 years; 25% female) underwent UET for acute limb
36
ischemia between 2014-2018. Rutherford Acute Limb Ischemia Classification was R1 in 56.3%,
37
R2a in 31.3%, and R2b in 12.5%. Etiology was thrombosis of native artery in 12.5% of patients,
38
prosthetic bypass in 31.3%, autogenous bypass in 6.3%, and stented native vessel in 50.0%.
39
Mean duration of thrombolytic therapy was 22.2 ± 11.3 hours, and mean tissue plasminogen
40
activator dose was 24.5 ± 15.3 mg. Major adverse limb events occurred in 16.7% of patients
41
within the first 30-days and 38.9% experienced a MALE by 1-year. Limb salvage at 30-days and
42
1-year was 93.8% and 87.5%, respectively. Ipsilateral reintervention was required in 12.5% of
43
patients within 30 days and 37.5% of patients within 1 year. Overall mortality was 6.2% at 30-
44
days and 13.5% at 1-year. In-line flow to the foot was re-established in 90.6% of patients, with a
45
significant improvement in pre- to post-op ABI (0.31+0.29 vs. 0.78+0.34, p<0.001) and number
46
of patent tibial runoff vessels (1.31+1.20 vs. 1.96+0.86, p <0.001). There was no significant
47
difference in revascularization success between occluded vessel types. All but one patient
48
required adjunctive therapy such as further thromboaspiration, stenting, or balloon angioplasty.
49
Major bleeding complications occurred in 3 patients (9.4%), including 1 intracranial hemorrhage
50
(3.1%).
51 52
Conclusions: UET with the EKOS device demonstrates acceptable real-world outcomes in the
53
treatment of acute limb ischemia. UET is generally safe and effective at re-establishing in line
54
flow to yield high limb salvage rates. However, UET is associated with a high rate of
55
reintervention. Further investigation is needed into specific predictors of limb salvage and need
56
for reintervention, as well as cost-efficacy of this technology compared to traditional methods.
57
58
Introduction
59
Acute limb ischemia (ALI) is an emergency diagnosis that generally requires immediate
60
intervention in order to avoid limb loss. No standard treatment algorithms exist, and a variety of
61
procedural options are available including catheter-directed thrombolysis (CDT), mechanical or
62
pharmacomechanical thrombectomy, and endovascular or open surgery. For patients who are
63
eligible, CDT with adjunctive endovascular therapy has demonstrated good short-term results
64
when compared with open surgery1,2, and is particularly effective at revascularization in patients
65
with less than 14 days of ischemia and those with non-autogenous bypasses3. Even with
66
immediate intervention and despite the advances in technology over the past decades, regardless
67
of the procedural approach amputation and death rates remain high in patients with a
68
presentation of ALI.4 Studies have found long-term outcomes of CDT to have high rates of
69
reintervention to preserve patency, amputation, and mortality at 1-, 5, and 10-year follow up5,6.
70
More recently, ultrasound-enhanced catheter-directed thrombolysis (UET) with the
71
EKOS Ekosonic® Endovascular System (EKOS Corporation, Bothell, WA) has been purported
72
in clinical trials to accelerate the fibrinolytic process in order to reduce treatment time and lytic
73
dosage in patients with ALI7,8. However, there are currently only a few small reports of its use in
74
a real-world clinical setting9–11. Herein we aim to add to this nascent body of literature and
75
present our institutional, multi-year experience with UET for ALI.
76 77 78
Methods After obtaining approval from the Institutional Review Board, we performed a
79
retrospective review of all patients undergoing UET for ALI at a single institution between
80
January 2014 and June 2018. All procedures were performed by vascular surgeons. Only patients
81
with ALI due to embolism or thrombosis of a native artery, bypass graft, or previous stent were
82
considered in the study. Patients who presented with ALI secondary to trauma or dissection were
83
excluded.
84
Data collected included patient demographics, co-morbidities and medications at the time
85
of presentation. Initial history & physical notes, discharge summaries, and clinic notes were
86
independently reviewed by two authors to assess presenting symptoms and duration, and the
87
persistence of any deficits or disability at follow-up. Operative reports were reviewed to obtain
88
procedural revascularization details including thrombolytic dosage, UET duration, and
89
endovascular or open adjuncts utilized in addition to UET.
90
Upon clinical diagnosis of ALI, patients were systemically heparinized and taken to the
91
endovascular suite for initial angiography and EKOS catheter placement for thrombolytic
92
infusion. In general, our institution’s UET protocol is to obtain contralateral common femoral
93
arterial access and then evaluate the ischemic limb angiographically to determine optimal
94
location for UET catheter placement and assess the patency of any runoff vessels. Next, a 6 Fr
95
sheath is placed up and over the aortic bifurcation and into the affected limb’s external iliac or
96
common femoral artery in order to stabilize the platform for overnight thrombolysis. The device
97
itself consists of a 5.2 Fr multi-lumen drug delivery catheter and a coaxial ultrasound core wire.
98
The active treatment zone of the catheter is available in lengths from 6 to 50 cm; catheter
99
selection was at the discretion of the operating surgeon and based on the length of the occlusion.
100
tPA is infused at 0.5-1 milligram per hour through the multi-lumen drug delivery catheter for
101
pharmacologic thrombolysis, saline is infused through the cooling port to prevent overheating
102
from the ultrasound, and 500 units/hr of unfractionated heparin is infused through the 6 Fr Ansel
103
sheath to prevent thrombus formation. Systemic heparinization is discontinued once UET is
104
initiated.
105
While undergoing UET, patients are monitored on a specially trained intermediate
106
intensive care unit where fibrinogen levels and coagulation parameters are checked every 6
107
hours, and neurovascular checks are performed every hour. Patients are treated with UET for a
108
variable period of time, typically overnight, and then taken back to the endovascular suite for a
109
lysis check to evaluate any progress in thrombus resolution and determine the need for possible
110
adjunctive interventions versus ongoing UET therapy. Completion angiography is routinely
111
performed at the conclusion of any intervention.
112
The primary endpoints for analysis were major adverse limb events (MALE), defined as
113
requiring reintervention and/or amputation, and mortality within 30-days and 1 year. Secondary
114
endpoints included technical success (i.e., re-establishing angiographic in-line flow to the foot),
115
use of adjunctive therapies, and postoperative complications, including major bleeding events..
116
Ankle-brachial indices (ABIs) were measured pre- and post-procedurally to document objective
117
change.
118
Basic descriptive statistics and paired Student’s t-tests were performed to compare pre-
119
and post-UET states, including ABI and the number of tibial runoff vessels. Unadjusted logistic
120
and linear regression models were used to evaluate associations between the primary and
121
secondary outcomes and: presentation, adjunctive therapies, procedural time and tissue
122
plasminogen activator (tPA) dosing, pre-operative and discharge medications, and type of vessel
123
intervened upon. Adjusted models were also created to evaluate associations with MALE and
124
mortality.
125
126 127
Results During the study period, 32 patients underwent UET for ALI. Mean age was 67.4 ± 14.9
128
years, and 8 (25%) were female. Patients had high prevalence of coronary artery disease
129
(43.8%), diabetes (46.9%), smoking (9.4% current, 43.8% former), and other co-morbidities.
130
Nearly half of patients (43.8%) were therapeutically anticoagulated at presentation, including
131
both warfarin (34.4%) and novel oral anticoagulants (NOACs; 9.4%). Half of patients (50.0%)
132
were taking clopidogrel, 59.4% were on aspirin, 18.7% of patients on neither clopidogrel nor
133
aspirin, and 28.1% were on a dual antiplatelet regimen. Three quarters of patients were on a
134
statin medication. Patient demographics, co-morbidities, and medications are summarized in
135
Table 1.
136
Rutherford ALI Classification was R1 in 18 patients (56.3%), R2a in 10 patients (31.3%),
137
and R2b in 4 patients (12.5%) patients. Median duration of symptoms for patients was 21.9 ± 25
138
days. The etiology of ALI was thrombosis of native artery in 4 patients (12.5%), stented native
139
vessel in 16 patients (50.0%), infrainguinal prosthetic bypass in 10 patients (31.2%), and
140
infrainguinal autogenous bypass in 2 patients (6.2%). The primary occlusion occurred at the
141
femoral-popliteal level in 31 patients (96.9%), and the tibial level in 1 patient (3.1%).
142
Mean duration of thrombolytic therapy was 22.2 ±11.2 hours and mean total tPA dose
143
was 24.5 ± 15.3 mg. No patients required premature cessation of therapy due to hemorrhagic
144
complications or developing concerningly abnormal fibrinogen or coagulation factor levels. Pre-
145
operative and procedural data are summarized in Table 2.
146 147
Major adverse limb events
148
Following UET, 16.7% of patients experienced a composite MALE within the first 30-
149
days and 38.9% experienced a MALE by 1-year. When MALE is broken down into its two
150
components of amputation and reintervention, limb salvage at 30-days and 1-year was 93.8%
151
and 87.5%, respectively. Two patients had major amputations during the initial encounter after
152
an unsuccessful revascularization.
153
The first patient was a 71-year-old gentleman who presented with R2a right lower
154
extremity ischemia secondary to a thrombosed popliteal aneurysm. After systemic heparinization
155
in the emergency department, initial angiography demonstrated no distal runoff and UET was
156
initiated using a 50cm EKOS catheter. However, overnight the patient continued to have
157
ischemic progression, his motor and sensory function of the right lower extremity deteriorated,
158
and it was judged that the limb could no longer be salvaged. The patient was taken to the
159
operating room for UET catheter removal and right below the knee amputation. Following the
160
procedure, the patient had a continued rise in his creatinine kinase with worsening renal function
161
and had non-viable appearing calf muscle on exam, ultimately necessitating a right above the
162
knee amputation.
163
The second patient requiring early amputation was an 87-year-old woman with chronic
164
critical limb threatening ischemia and an extensive vascular procedural history. The patient
165
presented with new, severe rest pain of her left foot and duplex ultrasound demonstrated an
166
occluded prosthetic femoral-popliteal bypass. Overnight UET using 16mg of tPA was successful
167
with completion angiogram demonstrating a patent bypass with single vessel in-line flow to the
168
foot. However, her symptoms returned the same evening and her bypass was found to have re-
169
occluded. Given her severely advanced disease and her minimally ambulatory status, the patient
170
and her family elected for her to undergo left below knee amputation.
171
Ipsilateral reintervention was required in 12.5% of patients in the first 30 days, and
172
37.5% within 1 year. Among the four patients who required early reintervention, one was a
173
stented vessel that required balloon angioplasty and stenting for residual stenosis, and three
174
patients (all prescribed oral anticoagulation) were re-thrombosed bypass grafts. Two out of the
175
three patients had balloon angioplasty only following the initial UET treatment and one had
176
angioplasty and stenting. These three patients successfully underwent UET again with the EKOS
177
system and all three patients received post-UET balloon angioplasty and stenting at the
178
conclusion of the cases to more durably address stenotic lesions. No further interventions were
179
performed at 1-year follow-up. In unadjusted logistic regression, occluded vessel type (p=0.90),
180
prior interventions (p=0.77), total number of adjuncts utilized (p=0.93), type of adjunct utilized
181
(p=0.62), and discharge on therapeutic anticoagulation (0.45) showed no statistically significant
182
association with early reintervention.
183
In unadjusted logistic regression, discharge on therapeutic anticoagulation (p=0.22),
184
Rutherford ALI stage at presentation (p=0.78), and number of additional adjunctive therapies
185
after UET (p=0.36) were not significantly associated with reintervention at any time point.
186
Similarly, neither tPA dose less than the median (p=0.63) nor thrombolysis time shorter than the
187
median (p=0.17) were significantly associated with reintervention.
188
Finally, logistic regression was performed to evaluate whether any patient or procedural
189
characteristics were associated with experiencing a MALE. Age, gender, and co-morbidities
190
(smoking history, hypertension, hyperlipidemia, atrial fibrillation, coronary artery disease,
191
cerebrovascular disease, renal failure, diabetes, and chronic obstructive pulmonary disease) were
192
evaluated. of which none of these on their own were significantly associated with higher
193
likelihood of experiencing a MALE at 30 days. However, at 1-year, patients who were actively
194
smoking (p=0.02) or had chronic obstructive pulmonary disease (p=0.03) were more likely to
195
experience a MALE. In terms of procedural factors, similar to the regressions performed for
196
reintervention discussed previously, at 30 days and at 1-year there were no significant
197
associations of adjunct utilization, occluded vessel type, or anticoagulation usage and suffering a
198
MALE.
199 200 201 202
Mortality Overall mortality was 6.2% at 30-days and 13.5% at 1-year. Two patients died within the first thirty days following intervention for ALI.
203
The first patient was an 83-year-old man who underwent successful left lower extremity
204
revascularization with UET. He received a total of 26mg of tPA over 24 hours. Twenty minutes
205
after procedure end time the patient developed unilateral hemiplegia, aphasia, and somnolence.
206
Emergent head CT demonstrated a large, acute intraparenchymal hematoma within the left
207
cerebral hemisphere, as well as multiple additional areas of acute hemorrhage within other lobes,
208
suggestive of underlying mass lesions from what was deemed to be likely occult metastatic
209
malignancy; however, the relationship of the large intraparenchymal hematoma to the suspected
210
metastatic disease is somewhat speculative in nature. Care was withdrawn several days later in
211
accordance with the patient’s goals of care.
212
The second patient was a 66-year-old man with a history of gastric neuroendocrine tumor
213
status post near total gastrectomy with Roux-en-Y gastrojejunostomy, prostate cancer status post
214
neoadjuvant chemotherapy and radical cysto-prostatectomy with neobladder creation, and newly
215
diagnosed metastatic urothelial cancer for which he was actively receiving chemotherapy. The
216
patient was also on warfarin for prior deep vein thrombosis. Despite therapeutic anticoagulation,
217
the patient developed extensive right femoral arterial thrombus causing R2a ischemic symptoms
218
and concerning for Trousseau’s syndrome. Although the patient’s prognosis was overall poor,
219
the oncologic team encouraged the vascular surgery service to proceed with any revascularizing
220
procedures felt to be of benefit. Hoping to avoid open intervention, the patient underwent UET
221
for a total of 48 hours and received 37 mg of tPA. This strategy achieved successful
222
thrombolysis of the right femoral artery without additional suction thrombectomy. He was
223
discharged on a regimen of Lovenox, clopidogrel, and aspirin to prevent future arterial or venous
224
thrombosis related to his malignancy; however, his right lower extremity thrombosed again a
225
week later. EKOS-mediated UET was again performed for 24 hours, and once successfully
226
revascularized the right superficial femoral artery was lined completely with Zilver PTX stents in
227
the hopes of maintaining in line flow to the tibial vessels for the remainder of the patient’s life.
228
The patient unfortunately passed away a month following the procedure due to rapid progression
229
of his aggressive metastatic urothelial cancer.
230
On unadjusted logistic regression, 30-day mortality was not (p=0.78) but 1-year mortality
231
was significantly higher in patients with Rutherford ALI class 2B at presentation (p=0.048);
232
however, this borderline significant effect disappeared once the model was adjusted for age,
233
gender, and co-morbidities (smoking history, hypertension, hyperlipidemia, atrial fibrillation,
234
coronary artery disease, cerebrovascular disease, renal failure, diabetes, and chronic obstructive
235
pulmonary disease). Most (81.2%) but not all patients were discharged on therapeutic
236
anticoagulation, and this was not associated with 1-year all-cause mortality (p=0.53).
237 238
Procedural Success and Revascularization
239
In-line flow to the foot was re-established in 29 patients (90.6%), with a significant
240
improvement from pre- to post-operative ABIs (0.30 + 0.29 vs. 0.78 + 0.34; p<0.001) and
241
number of patent tibial runoff vessels (1.31 + 1.20 vs. 1.96 + 0.86; p <0.001) (Figure 1). There
242
was no significant difference in procedural success between occluded vessel types (native vessel
243
75%, stented vessel 93.8%, autogenous bypass 100%, and prosthetic bypass 90%; p=0.48.)
244
All but one patient required adjunct therapies to establish in-line flow to the foot
245
following UET. The most common adjuncts were suction thrombectomy (50.0%) to remove any
246
residual thrombus, and balloon angioplasty (78.1%) and stent placement (40.6%) to address the
247
underlying failure points. No urgent surgical bypasses were performed. The decision to employ
248
adjunct therapies was made at the discretion of the operating surgeon in accordance with
249
standard practice.
250
However, in logistic regression, compared to UET alone, using one or more adjuncts was
251
not significantly associated with successful revascularization when the number of adjuncts was
252
evaluated as a continuous independent variable [OR 1.51, 95% CI 0.31-7.35, p = 0.61]. Use of
253
additional thromboaspiration was similarly not associated with successful revascularization in an
254
unadjusted logit model [OR 2.14, 95% CI 0.14-26.33, p=0.55]. Similarly, preoperative
255
pharmacotherapy regimen was also not significantly associated with successful
256
revascularization: outpatient oral therapeutic anticoagulation (p=0.92), aspirin (p=0.96),
257
clopidogrel (p=0.95), and dual antiplatelet therapy (p=0.94). In linear regression, the utilization
258
of more adjuncts was not significantly associated with a greater change in pre- and post-therapy
259
ABI measurements (p=0.64). Additionally, lower Rutherford ALI class at presentation was also
260
not predictive of success (p= 0.53). Neither longer treatment time nor higher doses of tPA
261
showed any significant advantage in achieving in line flow to the foot when both were evaluated
262
as continuous predictors (p=0.14 and p=0.86, respectively). When dichotomized into a binary
263
predictor above or below the median values for thrombolysis time and tPA dosing, there were
264
similarly no significant differences in the odds of successful revascularization (p=0.55 and
265
p=0.55, respectively).
266
Complications
267
Major bleeding complications occurred in 3 patients (9.4%), including two post-
268
procedural anemias requiring blood transfusion and one intracranial hemorrhage (3.1%), the
269
latter led to one of the aforementioned deaths. The two post-procedural anemias requiring
270
transfusion were not secondary to vascular access or retroperitoneal hematomas. No other major
271
complications were seen.
272 273 274
Discussion This series describes outcomes following the use of UET with the EKOS system for the
275
treatment of acute critical limb threatening ischemia due to arterial occlusion. Patients treated
276
with this modality had a very high rate of successful revascularization when treated first with
277
UET, as well as significant increases in both ABI and the number of tibial runoff vessels. The
278
effect also appeared to be clinically durable, with only two patients requiring ipsilateral major
279
amputation, both of whom failed initial revascularization attempts. Use of the EKOS system also
280
appears safe, with a low rate of bleeding complications and only one additional major adverse
281
cerebrovascular event noted in a patient with occult, presumably metastatic disease. In light of
282
the bleeding complications noted, the risks and benefits of UET, as with all systemic
283
anticoagulation and thrombolytic administration, should be weighed carefully prior to initiation
284
of therapy with special consideration given to patients with active or remissive malignancy.
285
Catheter-directed thrombolysis has been used to treat acute and subacute arterial
286
occlusion in clinical practice for some time. Randomized, controlled data has previously shown
287
favorable results in terms of successful revascularization and amputation-free survival, with the
288
best outcomes seen in patients with less than 14 days of symptom duration and non-autologous
289
bypasses3. Our results with the EKOS system are congruent with these findings, despite the
290
longer average ischemia time of 21 days and very long average lesion length of nearly 38 cm. In
291
fact, our successful revascularization rate of over 90% is higher than observed in the
292
aforementioned trial (84%), and more consistent with other contemporary EKOS data9,11. It is
293
worth noting that UET was not successful as a solo act, as all but one of our patients required
294
adjunct therapy and half underwent further suction thrombectomy. However, in the greater
295
context of vascular practice, UET demonstrated itself to be a useful component of an effective
296
treatment strategy and can be considered part of a larger armamentarium of techniques employed
297
to achieve in line flow to the foot in the acute setting.
298
Despite the longer ischemia time observed, the subacute duration of symptoms is
299
ultimately one of the presentation features that suggests to surgeons at our institution that EKOS
300
might be a successful first line therapy. If a patient has more than several days of pain and their
301
symptoms have not progressed to the point of irreversible damage, then in our experience the
302
EKOS system is effective for thrombolysis. We tend to use the EKOS system in patients who
303
present with lower Rutherford ALI classification, i.e. Rutherford 1 and 2a. The presence of rest
304
pain, sensory loss or muscle weakness indicating R2b ischemia generally persuades us to
305
perform immediate revascularization. An additional factor driving our decision to use EKOS is
306
whether the thrombosed vessel is native, stented or a bypass; we tend to use EKOS more
307
frequently in patients who have had a prior endovascular or open intervention with synthetic
308
material in place (either stent or bypass graft).
309
The use of ultrasound to enhance the effect of catheter directed thrombolysis is
310
predicated upon the idea that generating acoustic vibration will augment tPA delivery throughout
311
the thrombus. In theory, this could lead to lower tPA dosage with similar clinical efficacy, and
312
this has been shown in both venous thrombosis and pulmonary embolism12,13. There is relatively
313
little data on the use of UET in the arterial system, limited mostly to retrospective cohort
314
analyses such as the study from Chait et al10. Their series retrospectively compared EKOS with
315
standard CDT using a Unifuse catheter (Angiodynamics, Latham, NY), and found no differences
316
in either the required duration of therapy or tPA dose or the rate of successful revascularization.
317
Our series had a slightly higher success rate compared with their EKOS group (90.6% vs. 86%),
318
but with less tPA (24.5 vs. 48.2 mg) and shorter duration of therapy (22.2 vs 39.6 hours). Of
319
course, these results cannot actually be directly compared due to the retrospective nature of the
320
data, differences in study design and patient population, and use of adjunct therapies. However,
321
both series do suggest a high success rate with use of EKOS in this setting.
322
Although efficacious when utilized in conjunction with other endovascular technologies,
323
our study raises some questions regarding durability. Ipsilateral reintervention was required in
324
15.6% of patients in the first 30 days, and 37.5% within the first year. These rates are much
325
higher than seen in previous studies, where reported.9,14 The need for reintervention is
326
multifactorial, and certainly not uncommon in this population. It is not entirely clear why our
327
rates are so high but could be due to any combination of patient and anatomic factors. For
328
example, only 81.2% of patients in the study were discharged on therapeutic anticoagulation
329
after an episode of acute limb ischemia. Similarly, only ~80% of patients were on antiplatelet
330
agents and 75% on statins at presentation, considerably less than what might be expected of a
331
patient population who should most likely be on optimal medical therapy for secondary
332
cardiovascular risk reduction. Given these percentages, outpatient medication management could
333
represent a potential area for vascular practice improvement.
334
Cost is an additional consideration when comparing UET and traditional CDT. While a
335
formal cost analysis is beyond the scope of this study, the EKOS catheter system is certainly
336
more expensive than a simple, multi side-hole infusion catheter. However, this may be offset by
337
decreased drug dosage, and especially if there is decreased time spent in the interventional suite,
338
intensive care unit, and hospital. Further study into the hospital resources utilized both during
339
and after the interventions would be helpful in determining the relative costs associated with
340
each procedure and assist institutions in deciding which catheter to purchase.
341
There are several obvious limitations to this retrospective study. The main drawback is a
342
lack of a direct comparator group as a control. This is reflective of our group’s transition to the
343
EKOS system several years ago, which has led to nearly all recent cases of CDT being done with
344
EKOS. We did not feel it would be prudent to compare non-contemporaneous groups, due to the
345
number of confounders this could potentially introduce. Finally, our study involves a relatively
346
small number of patients, which limits its statistical power and our ability to perform subgroup
347
analyses.
348 349 350
Conclusions UET appears to be safe and effective in the treatment of acute limb ischemia secondary to
351
arterial occlusion in conjunction with other endovascular technologies in a real-world setting.
352
However, UET may be associated with high rates of reintervention. While the results of this and
353
other small studies are encouraging, more data are needed before declaring UET superior to
354
traditional CDT, especially with regard to cost-effectiveness.
355
356
References
357 358 359
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Taha AG, Byrne RM, Avgerinos ED, Marone LK, Makaroun MS, Chaer RA. Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia. J Vasc Surg. 2015 Jan;61(1):147–54.
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2.
Byrne RM, Taha AG, Avgerinos E, Marone LK, Makaroun MS, Chaer RA. Contemporary outcomes of endovascular interventions for acute limb ischemia. J Vasc Surg. 2014 Apr;59(4):988–95.
363 364 365
3.
Comerota AJ, Weaver FA, Hosking JD, Froehlich J, Folander H, Sussman B, et al. Results of a prospective, randomized trial of surgery versus thrombolysis for occluded lower extremity bypass grafts. Am J Surg. 1996 Aug;172(2):105–12.
366 367 368 369
4.
Baril DT, Ghosh K, Rosen AB. Trends in the incidence, treatment, and outcomes of acute lower extremity ischemia in the United States Medicare population. J Vasc Surg [Internet]. 2014 Sep 1 [cited 2019 Dec 30];60(3):669-677.e2. Available from: https://www.jvascsurg.org/article/S0741-5214(14)00658-2/abstract
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5.
Vakhitov D, Oksala N, Saarinen E, Vakhitov K, Salenius J-P, Suominen V. Survival of Patients and Treatment-Related Outcome After Intra-Arterial Thrombolysis for Acute Lower Limb Ischemia. Ann Vasc Surg. 2019 Feb;55:251–9.
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6.
Schrijver AM, de Vries J-PPM, van den Heuvel DAF, Moll FL. Long-Term Outcomes of Catheter-Directed Thrombolysis for Acute Lower Extremity Occlusions of Native Arteries and Prosthetic Bypass Grafts. Ann Vasc Surg. 2016 Feb;31:134–42.
376 377 378 379
7.
Schrijver AM, van Leersum M, Fioole B, Reijnen MMPJ, Hoksbergen AWJ, Vahl AC, et al. Dutch randomized trial comparing standard catheter-directed thrombolysis and ultrasound-accelerated thrombolysis for arterial thromboembolic infrainguinal disease (DUET). J Endovasc Ther Off J Int Soc Endovasc Spec. 2015 Feb;22(1):87–95.
380 381 382
8.
Wissgott C, Richter A, Kamusella P, Steinkamp HJ. Treatment of critical limb ischemia using ultrasound-enhanced thrombolysis (PARES Trial): final results. J Endovasc Ther Off J Int Soc Endovasc Spec. 2007 Aug;14(4):438–43.
383 384 385
9.
Schrijver A, Vos J, Hoksbergen AW, Fioole B, Fritschy W, Hulsebos R, et al. Ultrasoundaccelerated thrombolysis for lower extremity ischemia: multicenter experience and literature review. J Cardiovasc Surg (Torino). 2011 Aug;52(4):467–76.
386 387 388
10. Chait J, Aurshina A, Marks N, Hingorani A, Ascher E. Comparison of UltrasoundAccelerated Versus Multi-Hole Infusion Catheter-Directed Thrombolysis for the Treatment of Acute Limb Ischemia. Vasc Endovascular Surg. 2019 Jul 21;1538574419861768.
389 390 391
11. Schernthaner MB, Samuels S, Biegler P, Benenati JF, Uthoff H. Ultrasound-accelerated versus standard catheter-directed thrombolysis in 102 patients with acute and subacute limb ischemia. J Vasc Interv Radiol JVIR. 2014 Aug;25(8):1149–56; quiz 1157.
392 393 394
12. Parikh S, Motarjeme A, McNamara T, Raabe R, Hagspiel K, Benenati JF, et al. Ultrasoundaccelerated thrombolysis for the treatment of deep vein thrombosis: initial clinical experience. J Vasc Interv Radiol JVIR. 2008 Apr;19(4):521–8.
395 396 397 398
13. Lin PH, Annambhotla S, Bechara CF, Athamneh H, Weakley SM, Kobayashi K, et al. Comparison of percutaneous ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism. Vascular. 2009 Dec;17 Suppl 3:S137-147.
399 400 401
14. Lukasiewicz A, Lichota W, Thews M. Outcomes of accelerated catheter-directed thrombolysis in patients with acute arterial thrombosis. Vasc Med Lond Engl. 2016;21(5):453–8.
402
403
Figure and Table Legends
404 405 406 407 408 409
Figure 1. Improvement in Ankle-Brachial Index (ABI) and Tibial Runoff with UltrasoundEnhanced Thombolysis (UET). Pre- and Post-UET ABI (orange line) and number of tibial runoff vessels (blue bars) are shown. Both demonstrated significant increases with UET (p<0.001).
410 411 412
Table 1. Demographic Information and Comorbidities. ASA (American Society of Anesthesiologists); PTA (Percutaneous Transluminal Angioplasty).
413 414 415
Table 2. Pre-Operative and Procedural Details. ALI (Acute Limb Ischemia), PTA (Percutaneous Transluminal Angioplasty)
416
Table 1. Demographic Information and Comorbidities. ASA (American Society of Anesthesiologists); PTA (Percutaneous Transluminal Angioplasty). Demographic Female Gender (N, %) Age (Mean + SD) BMI (Mean + SD) Smoking (N, %) None Former Current Diabetes (N, %) Hypertension (N, %) Hyperlipidemia (N, %) Coronary artery disease (N, %) Atrial fibrillation (N, %) Cerebrovascular disease (N, %) Chronic kidney disease (N, %) Hemodialysis (N, %) Lung disease (N, %) ASA Class (N, %) I II III IV Prior Anticoagulation (N, %) Factor Xa Inhibitor Coumadin Aspirin Plavix Prior Ipsilateral Intervention (N, %) PTA/Stent Bypass Thrombolysis Occluded Vessel Type (N, %) Native Artery Prosthetic or Cryopreserved Artery Autogenous Bypass Stented Native Artery
8 (25) 67.4 + 14.9 26.8 15 (46.9) 14 (43.8) 3 (9.4) 15 (46.9) 26 (81.2) 23 (71.9) 14 (43.8) 3 (9.4) 7 (21.9) 12 (37.5) 0 6 (18.8) 2 (6.2) 8 (25) 20 (62.5) 2 (6.2) 3 (9.4) 11 (34.4) 19 (59.4) 16 (50) 21 (65.6) 14 (43.8) 4 (12.5) 4 (12.5) 10 (31.2) 2 (6.2) 16 (50)
Table 2. Pre-Operative and Procedural Details. ALI (Acute Limb Ischemia), PTA (Percutaneous Transluminal Angioplasty) Days of symptoms (Mean + SD) Occlusion length (Mean + SD) Rutherford ALI Classification (N, %) 1 2a 2b Level of Occlusion (N, %) Femoral-Popliteal Tibial Occluded Vessel Type (N, %) Native Artery Prosthetic or Cryopreserved Artery Autogenous Bypass Stented Native Artery Duration of Thrombolysis (Mean + SD) Tissue Plasminogen Activator Dose (Mean + SD) Adjunctive Procedures (N, %) PTA Stent Suction thrombectomy Embolectomy Bypass
21.9 + 25 d 37.6 + 18 cm 18 (56.3) 10 (31.3) 4 (12.5) 31 (96.9) 1 (3.1) 4 (12.5) 10 (31.2) 2 (6.2) 16 (50) 22.2 + 11.2 h 24.5 + 15.3 mg 25 (78.1) 13 (40.6) 16 (50) 2 (6.2) 0
S0890-5096(20)30003-0
DOI:
https://doi.org/10.1016/j.avsg.2019.12.026
Reference:
AVSG 4838
To appear in:
Annals of Vascular Surgery
Received Date: 15 November 2019 Revised Date:
30 December 2019
Accepted Date: 30 December 2019
Please cite this article as: George EL, Colvard B, Ho VT, Rothenberg KA, Lee JT, Stern JR, Real-World Outcomes of EKOS Ultrasound-Enhanced Catheter-Directed Thrombolysis for Acute Limb Ischemia, Annals of Vascular Surgery (2020), doi: https://doi.org/10.1016/j.avsg.2019.12.026. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
1
Real-World Outcomes of EKOS Ultrasound-Enhanced Catheter-Directed Thrombolysis
2
for Acute Limb Ischemia
3 4
Elizabeth L Georgea, Benjamin Colvarda, Vy-Thuy Hoa, Kara A Rothenbergb, Jason T Leea,
5
Jordan R Sterna
6 7
a
8
School of Medicine, Stanford, CA.
9
b
Department of Surgery, Division of Vascular & Endovascular Surgery. Stanford University
Department of Surgery, University of California San Francisco – East Bay. Oakland, CA.
10 11
Corresponding Author:
12
Jordan R. Stern, MD
13
Division of Vascular & Endovascular Surgery, Stanford University
14
300 Pasteur Drive, Alway M-121
15
Stanford, CA 94305
16
[email protected]
17 18
Keywords: ultrasound-enhanced catheter-directed thrombolysis, EKOS system, acute limb
19
ischemia
20
21
Abstract
22 23
Objectives: Ultrasound-enhanced catheter-directed thrombolysis (UET) using the EKOS device
24
for acute, peripheral arterial ischemia has been purported in clinical trials to accelerate the
25
fibrinolytic process in order to reduce treatment time and lytic dosage. We aim to describe
26
outcomes of UET in a real-world clinical setting.
27 28
Methods: We performed a retrospective review of all patients undergoing UET for acute limb
29
ischemia at a single institution. Data collected included patient demographics, procedural details,
30
and 30-day and 1-year outcomes. The primary endpoints for analysis were major adverse limb
31
events (MALE; reintervention and/or amputation) and mortality within 30-days and 1-year.
32
Secondary endpoints included technical success, use of adjunctive therapies, and postoperative
33
complications.
34 35
Results: 32 patients (mean age 67.4 ± 14.9 years; 25% female) underwent UET for acute limb
36
ischemia between 2014-2018. Rutherford Acute Limb Ischemia Classification was R1 in 56.3%,
37
R2a in 31.3%, and R2b in 12.5%. Etiology was thrombosis of native artery in 12.5% of patients,
38
prosthetic bypass in 31.3%, autogenous bypass in 6.3%, and stented native vessel in 50.0%.
39
Mean duration of thrombolytic therapy was 22.2 ± 11.3 hours, and mean tissue plasminogen
40
activator dose was 24.5 ± 15.3 mg. Major adverse limb events occurred in 16.7% of patients
41
within the first 30-days and 38.9% experienced a MALE by 1-year. Limb salvage at 30-days and
42
1-year was 93.8% and 87.5%, respectively. Ipsilateral reintervention was required in 12.5% of
43
patients within 30 days and 37.5% of patients within 1 year. Overall mortality was 6.2% at 30-
44
days and 13.5% at 1-year. In-line flow to the foot was re-established in 90.6% of patients, with a
45
significant improvement in pre- to post-op ABI (0.31+0.29 vs. 0.78+0.34, p<0.001) and number
46
of patent tibial runoff vessels (1.31+1.20 vs. 1.96+0.86, p <0.001). There was no significant
47
difference in revascularization success between occluded vessel types. All but one patient
48
required adjunctive therapy such as further thromboaspiration, stenting, or balloon angioplasty.
49
Major bleeding complications occurred in 3 patients (9.4%), including 1 intracranial hemorrhage
50
(3.1%).
51 52
Conclusions: UET with the EKOS device demonstrates acceptable real-world outcomes in the
53
treatment of acute limb ischemia. UET is generally safe and effective at re-establishing in line
54
flow to yield high limb salvage rates. However, UET is associated with a high rate of
55
reintervention. Further investigation is needed into specific predictors of limb salvage and need
56
for reintervention, as well as cost-efficacy of this technology compared to traditional methods.
57
58
Introduction
59
Acute limb ischemia (ALI) is an emergency diagnosis that generally requires immediate
60
intervention in order to avoid limb loss. No standard treatment algorithms exist, and a variety of
61
procedural options are available including catheter-directed thrombolysis (CDT), mechanical or
62
pharmacomechanical thrombectomy, and endovascular or open surgery. For patients who are
63
eligible, CDT with adjunctive endovascular therapy has demonstrated good short-term results
64
when compared with open surgery1,2, and is particularly effective at revascularization in patients
65
with less than 14 days of ischemia and those with non-autogenous bypasses3. Even with
66
immediate intervention and despite the advances in technology over the past decades, regardless
67
of the procedural approach amputation and death rates remain high in patients with a
68
presentation of ALI.4 Studies have found long-term outcomes of CDT to have high rates of
69
reintervention to preserve patency, amputation, and mortality at 1-, 5, and 10-year follow up5,6.
70
More recently, ultrasound-enhanced catheter-directed thrombolysis (UET) with the
71
EKOS Ekosonic® Endovascular System (EKOS Corporation, Bothell, WA) has been purported
72
in clinical trials to accelerate the fibrinolytic process in order to reduce treatment time and lytic
73
dosage in patients with ALI7,8. However, there are currently only a few small reports of its use in
74
a real-world clinical setting9–11. Herein we aim to add to this nascent body of literature and
75
present our institutional, multi-year experience with UET for ALI.
76 77 78
Methods After obtaining approval from the Institutional Review Board, we performed a
79
retrospective review of all patients undergoing UET for ALI at a single institution between
80
January 2014 and June 2018. All procedures were performed by vascular surgeons. Only patients
81
with ALI due to embolism or thrombosis of a native artery, bypass graft, or previous stent were
82
considered in the study. Patients who presented with ALI secondary to trauma or dissection were
83
excluded.
84
Data collected included patient demographics, co-morbidities and medications at the time
85
of presentation. Initial history & physical notes, discharge summaries, and clinic notes were
86
independently reviewed by two authors to assess presenting symptoms and duration, and the
87
persistence of any deficits or disability at follow-up. Operative reports were reviewed to obtain
88
procedural revascularization details including thrombolytic dosage, UET duration, and
89
endovascular or open adjuncts utilized in addition to UET.
90
Upon clinical diagnosis of ALI, patients were systemically heparinized and taken to the
91
endovascular suite for initial angiography and EKOS catheter placement for thrombolytic
92
infusion. In general, our institution’s UET protocol is to obtain contralateral common femoral
93
arterial access and then evaluate the ischemic limb angiographically to determine optimal
94
location for UET catheter placement and assess the patency of any runoff vessels. Next, a 6 Fr
95
sheath is placed up and over the aortic bifurcation and into the affected limb’s external iliac or
96
common femoral artery in order to stabilize the platform for overnight thrombolysis. The device
97
itself consists of a 5.2 Fr multi-lumen drug delivery catheter and a coaxial ultrasound core wire.
98
The active treatment zone of the catheter is available in lengths from 6 to 50 cm; catheter
99
selection was at the discretion of the operating surgeon and based on the length of the occlusion.
100
tPA is infused at 0.5-1 milligram per hour through the multi-lumen drug delivery catheter for
101
pharmacologic thrombolysis, saline is infused through the cooling port to prevent overheating
102
from the ultrasound, and 500 units/hr of unfractionated heparin is infused through the 6 Fr Ansel
103
sheath to prevent thrombus formation. Systemic heparinization is discontinued once UET is
104
initiated.
105
While undergoing UET, patients are monitored on a specially trained intermediate
106
intensive care unit where fibrinogen levels and coagulation parameters are checked every 6
107
hours, and neurovascular checks are performed every hour. Patients are treated with UET for a
108
variable period of time, typically overnight, and then taken back to the endovascular suite for a
109
lysis check to evaluate any progress in thrombus resolution and determine the need for possible
110
adjunctive interventions versus ongoing UET therapy. Completion angiography is routinely
111
performed at the conclusion of any intervention.
112
The primary endpoints for analysis were major adverse limb events (MALE), defined as
113
requiring reintervention and/or amputation, and mortality within 30-days and 1 year. Secondary
114
endpoints included technical success (i.e., re-establishing angiographic in-line flow to the foot),
115
use of adjunctive therapies, and postoperative complications, including major bleeding events..
116
Ankle-brachial indices (ABIs) were measured pre- and post-procedurally to document objective
117
change.
118
Basic descriptive statistics and paired Student’s t-tests were performed to compare pre-
119
and post-UET states, including ABI and the number of tibial runoff vessels. Unadjusted logistic
120
and linear regression models were used to evaluate associations between the primary and
121
secondary outcomes and: presentation, adjunctive therapies, procedural time and tissue
122
plasminogen activator (tPA) dosing, pre-operative and discharge medications, and type of vessel
123
intervened upon. Adjusted models were also created to evaluate associations with MALE and
124
mortality.
125
126 127
Results During the study period, 32 patients underwent UET for ALI. Mean age was 67.4 ± 14.9
128
years, and 8 (25%) were female. Patients had high prevalence of coronary artery disease
129
(43.8%), diabetes (46.9%), smoking (9.4% current, 43.8% former), and other co-morbidities.
130
Nearly half of patients (43.8%) were therapeutically anticoagulated at presentation, including
131
both warfarin (34.4%) and novel oral anticoagulants (NOACs; 9.4%). Half of patients (50.0%)
132
were taking clopidogrel, 59.4% were on aspirin, 18.7% of patients on neither clopidogrel nor
133
aspirin, and 28.1% were on a dual antiplatelet regimen. Three quarters of patients were on a
134
statin medication. Patient demographics, co-morbidities, and medications are summarized in
135
Table 1.
136
Rutherford ALI Classification was R1 in 18 patients (56.3%), R2a in 10 patients (31.3%),
137
and R2b in 4 patients (12.5%) patients. Median duration of symptoms for patients was 21.9 ± 25
138
days. The etiology of ALI was thrombosis of native artery in 4 patients (12.5%), stented native
139
vessel in 16 patients (50.0%), infrainguinal prosthetic bypass in 10 patients (31.2%), and
140
infrainguinal autogenous bypass in 2 patients (6.2%). The primary occlusion occurred at the
141
femoral-popliteal level in 31 patients (96.9%), and the tibial level in 1 patient (3.1%).
142
Mean duration of thrombolytic therapy was 22.2 ±11.2 hours and mean total tPA dose
143
was 24.5 ± 15.3 mg. No patients required premature cessation of therapy due to hemorrhagic
144
complications or developing concerningly abnormal fibrinogen or coagulation factor levels. Pre-
145
operative and procedural data are summarized in Table 2.
146 147
Major adverse limb events
148
Following UET, 16.7% of patients experienced a composite MALE within the first 30-
149
days and 38.9% experienced a MALE by 1-year. When MALE is broken down into its two
150
components of amputation and reintervention, limb salvage at 30-days and 1-year was 93.8%
151
and 87.5%, respectively. Two patients had major amputations during the initial encounter after
152
an unsuccessful revascularization.
153
The first patient was a 71-year-old gentleman who presented with R2a right lower
154
extremity ischemia secondary to a thrombosed popliteal aneurysm. After systemic heparinization
155
in the emergency department, initial angiography demonstrated no distal runoff and UET was
156
initiated using a 50cm EKOS catheter. However, overnight the patient continued to have
157
ischemic progression, his motor and sensory function of the right lower extremity deteriorated,
158
and it was judged that the limb could no longer be salvaged. The patient was taken to the
159
operating room for UET catheter removal and right below the knee amputation. Following the
160
procedure, the patient had a continued rise in his creatinine kinase with worsening renal function
161
and had non-viable appearing calf muscle on exam, ultimately necessitating a right above the
162
knee amputation.
163
The second patient requiring early amputation was an 87-year-old woman with chronic
164
critical limb threatening ischemia and an extensive vascular procedural history. The patient
165
presented with new, severe rest pain of her left foot and duplex ultrasound demonstrated an
166
occluded prosthetic femoral-popliteal bypass. Overnight UET using 16mg of tPA was successful
167
with completion angiogram demonstrating a patent bypass with single vessel in-line flow to the
168
foot. However, her symptoms returned the same evening and her bypass was found to have re-
169
occluded. Given her severely advanced disease and her minimally ambulatory status, the patient
170
and her family elected for her to undergo left below knee amputation.
171
Ipsilateral reintervention was required in 12.5% of patients in the first 30 days, and
172
37.5% within 1 year. Among the four patients who required early reintervention, one was a
173
stented vessel that required balloon angioplasty and stenting for residual stenosis, and three
174
patients (all prescribed oral anticoagulation) were re-thrombosed bypass grafts. Two out of the
175
three patients had balloon angioplasty only following the initial UET treatment and one had
176
angioplasty and stenting. These three patients successfully underwent UET again with the EKOS
177
system and all three patients received post-UET balloon angioplasty and stenting at the
178
conclusion of the cases to more durably address stenotic lesions. No further interventions were
179
performed at 1-year follow-up. In unadjusted logistic regression, occluded vessel type (p=0.90),
180
prior interventions (p=0.77), total number of adjuncts utilized (p=0.93), type of adjunct utilized
181
(p=0.62), and discharge on therapeutic anticoagulation (0.45) showed no statistically significant
182
association with early reintervention.
183
In unadjusted logistic regression, discharge on therapeutic anticoagulation (p=0.22),
184
Rutherford ALI stage at presentation (p=0.78), and number of additional adjunctive therapies
185
after UET (p=0.36) were not significantly associated with reintervention at any time point.
186
Similarly, neither tPA dose less than the median (p=0.63) nor thrombolysis time shorter than the
187
median (p=0.17) were significantly associated with reintervention.
188
Finally, logistic regression was performed to evaluate whether any patient or procedural
189
characteristics were associated with experiencing a MALE. Age, gender, and co-morbidities
190
(smoking history, hypertension, hyperlipidemia, atrial fibrillation, coronary artery disease,
191
cerebrovascular disease, renal failure, diabetes, and chronic obstructive pulmonary disease) were
192
evaluated. of which none of these on their own were significantly associated with higher
193
likelihood of experiencing a MALE at 30 days. However, at 1-year, patients who were actively
194
smoking (p=0.02) or had chronic obstructive pulmonary disease (p=0.03) were more likely to
195
experience a MALE. In terms of procedural factors, similar to the regressions performed for
196
reintervention discussed previously, at 30 days and at 1-year there were no significant
197
associations of adjunct utilization, occluded vessel type, or anticoagulation usage and suffering a
198
MALE.
199 200 201 202
Mortality Overall mortality was 6.2% at 30-days and 13.5% at 1-year. Two patients died within the first thirty days following intervention for ALI.
203
The first patient was an 83-year-old man who underwent successful left lower extremity
204
revascularization with UET. He received a total of 26mg of tPA over 24 hours. Twenty minutes
205
after procedure end time the patient developed unilateral hemiplegia, aphasia, and somnolence.
206
Emergent head CT demonstrated a large, acute intraparenchymal hematoma within the left
207
cerebral hemisphere, as well as multiple additional areas of acute hemorrhage within other lobes,
208
suggestive of underlying mass lesions from what was deemed to be likely occult metastatic
209
malignancy; however, the relationship of the large intraparenchymal hematoma to the suspected
210
metastatic disease is somewhat speculative in nature. Care was withdrawn several days later in
211
accordance with the patient’s goals of care.
212
The second patient was a 66-year-old man with a history of gastric neuroendocrine tumor
213
status post near total gastrectomy with Roux-en-Y gastrojejunostomy, prostate cancer status post
214
neoadjuvant chemotherapy and radical cysto-prostatectomy with neobladder creation, and newly
215
diagnosed metastatic urothelial cancer for which he was actively receiving chemotherapy. The
216
patient was also on warfarin for prior deep vein thrombosis. Despite therapeutic anticoagulation,
217
the patient developed extensive right femoral arterial thrombus causing R2a ischemic symptoms
218
and concerning for Trousseau’s syndrome. Although the patient’s prognosis was overall poor,
219
the oncologic team encouraged the vascular surgery service to proceed with any revascularizing
220
procedures felt to be of benefit. Hoping to avoid open intervention, the patient underwent UET
221
for a total of 48 hours and received 37 mg of tPA. This strategy achieved successful
222
thrombolysis of the right femoral artery without additional suction thrombectomy. He was
223
discharged on a regimen of Lovenox, clopidogrel, and aspirin to prevent future arterial or venous
224
thrombosis related to his malignancy; however, his right lower extremity thrombosed again a
225
week later. EKOS-mediated UET was again performed for 24 hours, and once successfully
226
revascularized the right superficial femoral artery was lined completely with Zilver PTX stents in
227
the hopes of maintaining in line flow to the tibial vessels for the remainder of the patient’s life.
228
The patient unfortunately passed away a month following the procedure due to rapid progression
229
of his aggressive metastatic urothelial cancer.
230
On unadjusted logistic regression, 30-day mortality was not (p=0.78) but 1-year mortality
231
was significantly higher in patients with Rutherford ALI class 2B at presentation (p=0.048);
232
however, this borderline significant effect disappeared once the model was adjusted for age,
233
gender, and co-morbidities (smoking history, hypertension, hyperlipidemia, atrial fibrillation,
234
coronary artery disease, cerebrovascular disease, renal failure, diabetes, and chronic obstructive
235
pulmonary disease). Most (81.2%) but not all patients were discharged on therapeutic
236
anticoagulation, and this was not associated with 1-year all-cause mortality (p=0.53).
237 238
Procedural Success and Revascularization
239
In-line flow to the foot was re-established in 29 patients (90.6%), with a significant
240
improvement from pre- to post-operative ABIs (0.30 + 0.29 vs. 0.78 + 0.34; p<0.001) and
241
number of patent tibial runoff vessels (1.31 + 1.20 vs. 1.96 + 0.86; p <0.001) (Figure 1). There
242
was no significant difference in procedural success between occluded vessel types (native vessel
243
75%, stented vessel 93.8%, autogenous bypass 100%, and prosthetic bypass 90%; p=0.48.)
244
All but one patient required adjunct therapies to establish in-line flow to the foot
245
following UET. The most common adjuncts were suction thrombectomy (50.0%) to remove any
246
residual thrombus, and balloon angioplasty (78.1%) and stent placement (40.6%) to address the
247
underlying failure points. No urgent surgical bypasses were performed. The decision to employ
248
adjunct therapies was made at the discretion of the operating surgeon in accordance with
249
standard practice.
250
However, in logistic regression, compared to UET alone, using one or more adjuncts was
251
not significantly associated with successful revascularization when the number of adjuncts was
252
evaluated as a continuous independent variable [OR 1.51, 95% CI 0.31-7.35, p = 0.61]. Use of
253
additional thromboaspiration was similarly not associated with successful revascularization in an
254
unadjusted logit model [OR 2.14, 95% CI 0.14-26.33, p=0.55]. Similarly, preoperative
255
pharmacotherapy regimen was also not significantly associated with successful
256
revascularization: outpatient oral therapeutic anticoagulation (p=0.92), aspirin (p=0.96),
257
clopidogrel (p=0.95), and dual antiplatelet therapy (p=0.94). In linear regression, the utilization
258
of more adjuncts was not significantly associated with a greater change in pre- and post-therapy
259
ABI measurements (p=0.64). Additionally, lower Rutherford ALI class at presentation was also
260
not predictive of success (p= 0.53). Neither longer treatment time nor higher doses of tPA
261
showed any significant advantage in achieving in line flow to the foot when both were evaluated
262
as continuous predictors (p=0.14 and p=0.86, respectively). When dichotomized into a binary
263
predictor above or below the median values for thrombolysis time and tPA dosing, there were
264
similarly no significant differences in the odds of successful revascularization (p=0.55 and
265
p=0.55, respectively).
266
Complications
267
Major bleeding complications occurred in 3 patients (9.4%), including two post-
268
procedural anemias requiring blood transfusion and one intracranial hemorrhage (3.1%), the
269
latter led to one of the aforementioned deaths. The two post-procedural anemias requiring
270
transfusion were not secondary to vascular access or retroperitoneal hematomas. No other major
271
complications were seen.
272 273 274
Discussion This series describes outcomes following the use of UET with the EKOS system for the
275
treatment of acute critical limb threatening ischemia due to arterial occlusion. Patients treated
276
with this modality had a very high rate of successful revascularization when treated first with
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UET, as well as significant increases in both ABI and the number of tibial runoff vessels. The
278
effect also appeared to be clinically durable, with only two patients requiring ipsilateral major
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amputation, both of whom failed initial revascularization attempts. Use of the EKOS system also
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appears safe, with a low rate of bleeding complications and only one additional major adverse
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cerebrovascular event noted in a patient with occult, presumably metastatic disease. In light of
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the bleeding complications noted, the risks and benefits of UET, as with all systemic
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anticoagulation and thrombolytic administration, should be weighed carefully prior to initiation
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of therapy with special consideration given to patients with active or remissive malignancy.
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Catheter-directed thrombolysis has been used to treat acute and subacute arterial
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occlusion in clinical practice for some time. Randomized, controlled data has previously shown
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favorable results in terms of successful revascularization and amputation-free survival, with the
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best outcomes seen in patients with less than 14 days of symptom duration and non-autologous
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bypasses3. Our results with the EKOS system are congruent with these findings, despite the
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longer average ischemia time of 21 days and very long average lesion length of nearly 38 cm. In
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fact, our successful revascularization rate of over 90% is higher than observed in the
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aforementioned trial (84%), and more consistent with other contemporary EKOS data9,11. It is
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worth noting that UET was not successful as a solo act, as all but one of our patients required
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adjunct therapy and half underwent further suction thrombectomy. However, in the greater
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context of vascular practice, UET demonstrated itself to be a useful component of an effective
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treatment strategy and can be considered part of a larger armamentarium of techniques employed
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to achieve in line flow to the foot in the acute setting.
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Despite the longer ischemia time observed, the subacute duration of symptoms is
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ultimately one of the presentation features that suggests to surgeons at our institution that EKOS
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might be a successful first line therapy. If a patient has more than several days of pain and their
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symptoms have not progressed to the point of irreversible damage, then in our experience the
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EKOS system is effective for thrombolysis. We tend to use the EKOS system in patients who
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present with lower Rutherford ALI classification, i.e. Rutherford 1 and 2a. The presence of rest
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pain, sensory loss or muscle weakness indicating R2b ischemia generally persuades us to
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perform immediate revascularization. An additional factor driving our decision to use EKOS is
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whether the thrombosed vessel is native, stented or a bypass; we tend to use EKOS more
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frequently in patients who have had a prior endovascular or open intervention with synthetic
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material in place (either stent or bypass graft).
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The use of ultrasound to enhance the effect of catheter directed thrombolysis is
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predicated upon the idea that generating acoustic vibration will augment tPA delivery throughout
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the thrombus. In theory, this could lead to lower tPA dosage with similar clinical efficacy, and
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this has been shown in both venous thrombosis and pulmonary embolism12,13. There is relatively
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little data on the use of UET in the arterial system, limited mostly to retrospective cohort
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analyses such as the study from Chait et al10. Their series retrospectively compared EKOS with
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standard CDT using a Unifuse catheter (Angiodynamics, Latham, NY), and found no differences
316
in either the required duration of therapy or tPA dose or the rate of successful revascularization.
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Our series had a slightly higher success rate compared with their EKOS group (90.6% vs. 86%),
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but with less tPA (24.5 vs. 48.2 mg) and shorter duration of therapy (22.2 vs 39.6 hours). Of
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course, these results cannot actually be directly compared due to the retrospective nature of the
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data, differences in study design and patient population, and use of adjunct therapies. However,
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both series do suggest a high success rate with use of EKOS in this setting.
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Although efficacious when utilized in conjunction with other endovascular technologies,
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our study raises some questions regarding durability. Ipsilateral reintervention was required in
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15.6% of patients in the first 30 days, and 37.5% within the first year. These rates are much
325
higher than seen in previous studies, where reported.9,14 The need for reintervention is
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multifactorial, and certainly not uncommon in this population. It is not entirely clear why our
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rates are so high but could be due to any combination of patient and anatomic factors. For
328
example, only 81.2% of patients in the study were discharged on therapeutic anticoagulation
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after an episode of acute limb ischemia. Similarly, only ~80% of patients were on antiplatelet
330
agents and 75% on statins at presentation, considerably less than what might be expected of a
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patient population who should most likely be on optimal medical therapy for secondary
332
cardiovascular risk reduction. Given these percentages, outpatient medication management could
333
represent a potential area for vascular practice improvement.
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Cost is an additional consideration when comparing UET and traditional CDT. While a
335
formal cost analysis is beyond the scope of this study, the EKOS catheter system is certainly
336
more expensive than a simple, multi side-hole infusion catheter. However, this may be offset by
337
decreased drug dosage, and especially if there is decreased time spent in the interventional suite,
338
intensive care unit, and hospital. Further study into the hospital resources utilized both during
339
and after the interventions would be helpful in determining the relative costs associated with
340
each procedure and assist institutions in deciding which catheter to purchase.
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There are several obvious limitations to this retrospective study. The main drawback is a
342
lack of a direct comparator group as a control. This is reflective of our group’s transition to the
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EKOS system several years ago, which has led to nearly all recent cases of CDT being done with
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EKOS. We did not feel it would be prudent to compare non-contemporaneous groups, due to the
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number of confounders this could potentially introduce. Finally, our study involves a relatively
346
small number of patients, which limits its statistical power and our ability to perform subgroup
347
analyses.
348 349 350
Conclusions UET appears to be safe and effective in the treatment of acute limb ischemia secondary to
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arterial occlusion in conjunction with other endovascular technologies in a real-world setting.
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However, UET may be associated with high rates of reintervention. While the results of this and
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other small studies are encouraging, more data are needed before declaring UET superior to
354
traditional CDT, especially with regard to cost-effectiveness.
355
356
References
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Taha AG, Byrne RM, Avgerinos ED, Marone LK, Makaroun MS, Chaer RA. Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia. J Vasc Surg. 2015 Jan;61(1):147–54.
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Byrne RM, Taha AG, Avgerinos E, Marone LK, Makaroun MS, Chaer RA. Contemporary outcomes of endovascular interventions for acute limb ischemia. J Vasc Surg. 2014 Apr;59(4):988–95.
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Comerota AJ, Weaver FA, Hosking JD, Froehlich J, Folander H, Sussman B, et al. Results of a prospective, randomized trial of surgery versus thrombolysis for occluded lower extremity bypass grafts. Am J Surg. 1996 Aug;172(2):105–12.
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Baril DT, Ghosh K, Rosen AB. Trends in the incidence, treatment, and outcomes of acute lower extremity ischemia in the United States Medicare population. J Vasc Surg [Internet]. 2014 Sep 1 [cited 2019 Dec 30];60(3):669-677.e2. Available from: https://www.jvascsurg.org/article/S0741-5214(14)00658-2/abstract
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Vakhitov D, Oksala N, Saarinen E, Vakhitov K, Salenius J-P, Suominen V. Survival of Patients and Treatment-Related Outcome After Intra-Arterial Thrombolysis for Acute Lower Limb Ischemia. Ann Vasc Surg. 2019 Feb;55:251–9.
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Schrijver AM, de Vries J-PPM, van den Heuvel DAF, Moll FL. Long-Term Outcomes of Catheter-Directed Thrombolysis for Acute Lower Extremity Occlusions of Native Arteries and Prosthetic Bypass Grafts. Ann Vasc Surg. 2016 Feb;31:134–42.
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Schrijver AM, van Leersum M, Fioole B, Reijnen MMPJ, Hoksbergen AWJ, Vahl AC, et al. Dutch randomized trial comparing standard catheter-directed thrombolysis and ultrasound-accelerated thrombolysis for arterial thromboembolic infrainguinal disease (DUET). J Endovasc Ther Off J Int Soc Endovasc Spec. 2015 Feb;22(1):87–95.
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Wissgott C, Richter A, Kamusella P, Steinkamp HJ. Treatment of critical limb ischemia using ultrasound-enhanced thrombolysis (PARES Trial): final results. J Endovasc Ther Off J Int Soc Endovasc Spec. 2007 Aug;14(4):438–43.
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Schrijver A, Vos J, Hoksbergen AW, Fioole B, Fritschy W, Hulsebos R, et al. Ultrasoundaccelerated thrombolysis for lower extremity ischemia: multicenter experience and literature review. J Cardiovasc Surg (Torino). 2011 Aug;52(4):467–76.
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10. Chait J, Aurshina A, Marks N, Hingorani A, Ascher E. Comparison of UltrasoundAccelerated Versus Multi-Hole Infusion Catheter-Directed Thrombolysis for the Treatment of Acute Limb Ischemia. Vasc Endovascular Surg. 2019 Jul 21;1538574419861768.
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11. Schernthaner MB, Samuels S, Biegler P, Benenati JF, Uthoff H. Ultrasound-accelerated versus standard catheter-directed thrombolysis in 102 patients with acute and subacute limb ischemia. J Vasc Interv Radiol JVIR. 2014 Aug;25(8):1149–56; quiz 1157.
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12. Parikh S, Motarjeme A, McNamara T, Raabe R, Hagspiel K, Benenati JF, et al. Ultrasoundaccelerated thrombolysis for the treatment of deep vein thrombosis: initial clinical experience. J Vasc Interv Radiol JVIR. 2008 Apr;19(4):521–8.
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Figure and Table Legends
404 405 406 407 408 409
Figure 1. Improvement in Ankle-Brachial Index (ABI) and Tibial Runoff with UltrasoundEnhanced Thombolysis (UET). Pre- and Post-UET ABI (orange line) and number of tibial runoff vessels (blue bars) are shown. Both demonstrated significant increases with UET (p<0.001).
410 411 412
Table 1. Demographic Information and Comorbidities. ASA (American Society of Anesthesiologists); PTA (Percutaneous Transluminal Angioplasty).
413 414 415
Table 2. Pre-Operative and Procedural Details. ALI (Acute Limb Ischemia), PTA (Percutaneous Transluminal Angioplasty)
416
Table 1. Demographic Information and Comorbidities. ASA (American Society of Anesthesiologists); PTA (Percutaneous Transluminal Angioplasty). Demographic Female Gender (N, %) Age (Mean + SD) BMI (Mean + SD) Smoking (N, %) None Former Current Diabetes (N, %) Hypertension (N, %) Hyperlipidemia (N, %) Coronary artery disease (N, %) Atrial fibrillation (N, %) Cerebrovascular disease (N, %) Chronic kidney disease (N, %) Hemodialysis (N, %) Lung disease (N, %) ASA Class (N, %) I II III IV Prior Anticoagulation (N, %) Factor Xa Inhibitor Coumadin Aspirin Plavix Prior Ipsilateral Intervention (N, %) PTA/Stent Bypass Thrombolysis Occluded Vessel Type (N, %) Native Artery Prosthetic or Cryopreserved Artery Autogenous Bypass Stented Native Artery
8 (25) 67.4 + 14.9 26.8 15 (46.9) 14 (43.8) 3 (9.4) 15 (46.9) 26 (81.2) 23 (71.9) 14 (43.8) 3 (9.4) 7 (21.9) 12 (37.5) 0 6 (18.8) 2 (6.2) 8 (25) 20 (62.5) 2 (6.2) 3 (9.4) 11 (34.4) 19 (59.4) 16 (50) 21 (65.6) 14 (43.8) 4 (12.5) 4 (12.5) 10 (31.2) 2 (6.2) 16 (50)
Table 2. Pre-Operative and Procedural Details. ALI (Acute Limb Ischemia), PTA (Percutaneous Transluminal Angioplasty) Days of symptoms (Mean + SD) Occlusion length (Mean + SD) Rutherford ALI Classification (N, %) 1 2a 2b Level of Occlusion (N, %) Femoral-Popliteal Tibial Occluded Vessel Type (N, %) Native Artery Prosthetic or Cryopreserved Artery Autogenous Bypass Stented Native Artery Duration of Thrombolysis (Mean + SD) Tissue Plasminogen Activator Dose (Mean + SD) Adjunctive Procedures (N, %) PTA Stent Suction thrombectomy Embolectomy Bypass
21.9 + 25 d 37.6 + 18 cm 18 (56.3) 10 (31.3) 4 (12.5) 31 (96.9) 1 (3.1) 4 (12.5) 10 (31.2) 2 (6.2) 16 (50) 22.2 + 11.2 h 24.5 + 15.3 mg 25 (78.1) 13 (40.6) 16 (50) 2 (6.2) 0