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Ultrasound Aspects and Recanalization Rates in Patients with Lower-Limb Deep Venous Thrombosis Treated with Rivaroxaban
Journal Pre-proof Ultrasound aspects and Recanalization Rates in Patients with Lower-limb Deep Venous Thrombosis Treated with Rivaroxaban Rafael de Athayde Soares, M.D, Marcelo Fernando Matielo, PhD, Francisco Cardoso Brochado Neto, PhD, Rogério Duque Almeida, M.D, Roberto Sacilotto, PhD PII:
S0890-5096(20)30037-6
DOI:
https://doi.org/10.1016/j.avsg.2020.01.017
Reference:
AVSG 4872
To appear in:
Annals of Vascular Surgery
Received Date: 16 November 2019 Revised Date:
1 January 2020
Accepted Date: 6 January 2020
Please cite this article as: de Athayde Soares R, Matielo MF, Brochado Neto FC, Almeida RD, Sacilotto R, Ultrasound aspects and Recanalization Rates in Patients with Lower-limb Deep Venous Thrombosis Treated with Rivaroxaban, Annals of Vascular Surgery (2020), doi: https://doi.org/10.1016/ j.avsg.2020.01.017. 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.
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Clinical Research
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Ultrasound aspects and Recanalization Rates in Patients with Lower-limb Deep
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Venous Thrombosis Treated with Rivaroxaban
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Rafael de Athayde Soares, M.D. Hospital do Servidor Público Estadual de São Paulo
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Email: [email protected] Phone: +5511999813931
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(Corresponding Author)
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Marcelo Fernando Matielo, PhD, Hospital do Servidor Público Estadual de São Paulo
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Francisco Cardoso Brochado Neto, PhD, Hospital do Servidor Público Estadual de
9
São Paulo.
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Rogério Duque Almeida, M.D, Hospital do Servidor Público Estadual de São Paulo
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Roberto Sacilotto, PhD, Hospital do Servidor Público Estadual de São Paulo
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
1
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Abstract
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OBJECTIVES In this paper, we report the Ultrasound aspects and Recanalization
31
Rates of patients with deep venous thrombosis (DVT) in the lower limbs treated with
32
the rivaroxaban, focusing on the recanalization rate and the ultrassonographic aspects.
33
METHODS This was a prospective, consecutive cohort study of patients admitted
34
with DVT who were submitted to treatment with Rivaroxaban for 6 months to the
35
Division of Vascular and Endovascular Surgery, Hospital do Servidor Público
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Estadual, São Paulo, Brazil, between march 2016 and July 2018.
37
RESULTS Fifty-one patients with DVT were admitted to the Vascular Surgery
38
Department and received Rivaroxaban for 6 months. The follow-up time was 360
39
days. Analyses were performed at 180 and 360 days. The rate of total venous
40
recanalization at 360 days was 76.4% (39 patients). The incidence of partial venous
41
recanalization was 23.5% (12 patients). At the first month, 11 patients (21.7%)
42
continued with total occlusion of the vein, with 4 patients (6.5%) with no residual
43
thrombi. However, at 6 months only 2 patients (2.2%) continued with total occlusion
44
of the vein, with 26 patients (47.8%) with no residual thrombi. At 12 months, there
45
were 39 patients (76.4%) with no residual thrombi. Univariate and multivariable
46
logistic regression identified the following factors related to total venous
47
recanalization: the absence of popliteal vein reflux (p = 0.007; OR = 0.386), no
48
residual thrombi (p = 0.008; OR = 3.213), femoropopliteal clot length at 1 month ( p =
49
0.016; OR = 3.021), femoropopliteal clot length at 6 months (OR = 2.234, p = 0.008),.
50
The incidence of PTS at 12 months was 8.3%.
51 52
CONCLUSIONS In this study, patients who received oral rivaroxaban displayed
53
satisfatory total vein recanalization rate after 6 months and 12 months. The factors
2
54
associated with better total recanalization rates were the absence of popliteal vein
55
reflux, absence of residual thrombi in the veins, femoropopliteal clot length at 1
56
month ( p = 0.016; OR = 3.021), femoropopliteal clot length at 6 months (OR = 2.234,
57
p = 0.008). Moreover, the incidence of PTS at 12 months was 8.3%.
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
3
76 77
Introduction The treatment for Deep venous thrombosis (DVT) has developed substantially
78
during the last years, mainly due to the new anticoagulation drugs available for the
79
treatment of this common and dreadful condition. Since the publication of the
80
EINSTEIN Clinical Trial Program,1 rivaroxaban has shown to be at least as effective
81
as enoxaparin/vitamin K antagonist in the acute treatment and secondary prevention
82
of recurrent venous thromboembolism in patients with creatinine clearance > 30
83
mL/min.1,2
84
The ultrasound aspects of the evolution of the DVT plays an important role in
85
the prognostic factors related to the outcomes of this disease. According to Dronkers
86
et al,3 two ultrasonographic parameters measured during or after the treatment of
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DVT in the leg predicted post thrombotic syndrome (PTS): residual vein thrombosis
88
(pooled OR, 2.17) and venous reflux at the popliteal level (pooled OR, 1.34). These
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ultrassonographic findings correlates with important clinical prognostic of the DVT,
90
mainly due to the high risk of the development of PTS, a condition related to poorer
91
clinical evolution of the patients. Another study by Jeraj et al4 suggested that patients
92
with residual thrombi were at greater risk of PTS than patients with total vein
93
recanalization (OR, 6.0; p = 0.006). No difference in the presence of femoral neither
94
popliteal reflux was observed in these patients.
95
There are few studies in the literature telling about the new anticoagulation
96
drugs for treatment of DVT and the recanalization rates or ultrasound aspects of this
97
treatment. Therefore, the objective of this study was to evaluate the recanalization rate
98
measured with duplex ultrasound (DUS) and the ultrasound aspects in patients
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suffering from DVT who were treated with oral rivaroxaban.
100
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101
Methods
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This study was approved by the Research Ethics Committee of the Hospital do
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Servidor Público Estadual, São Paulo, Brazil. This prospective, consecutive, cohort
104
study included patients treated for acute iliofemoral and/or femoropopliteal DVT of a
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lower limb at the Division of Vascular and Endovascular Surgery, Hospital do
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Servidor Público Estadual, São Paulo, Brazil, between march 2016 and July 2018.
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Patient informed consent was obtained for the study, according to the principles
108
outlines in the Declaration to Helsink. The patient data were collected during an
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appointment at the routine follow-up, and recorded with the proper protocols. The
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data obtained included the patient’s general and demographic characteristics, and the
111
information recorded during the outpatient follow-up visits. This research received no
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specific funding.
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The non-inclusion criteria were: pregnancy, age < 18 years or > 80 years,
114
chronic renal failure, chronic hepatic failure, inferior vena cava thrombosis,
115
contraindication for any type of anticoagulation, previous DVT on the ipsilateral
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affected limb, or any type of active cancer, patients who refused to participate in the
117
study.
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The exclusion criteria were pre-defined prior to the start of the study and were
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defined as: several hemorrhagic complications that required the discontinuation of
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anticoagulation, death after < 30 days, allergic reaction to any anticoagulant, a
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diagnosis of active cancer during follow-up, loss to follow-up.
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The diagnosis of DVT was made with clinical signs and symptoms, laboratory
123
tests such as D-dimer, and routine DUS of the affected limb. The criteria used to
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confirm acute DVT with DUS were the absence or diminution of venous flow,
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incompressibility of the vessel, visible thrombus, enlarged vein diameter, immobility
5
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of the valves, and loss of respiratory phasicity.5 All DUS were performed by a single
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examination, vascular surgeon, blinded physician.
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All the patients diagnosed with acute DVT were hospitalized and received
129
initial anticoagulation with subcutaneous enoxaparin (1 mg/kg/dose) every 12 h
130
(12/12 h) or intravenous unfractionated heparin (IUH) (loading dose 80 UI/kg, and 18
131
UI/kg/h) for at least 48–72 h. The infusion dose of IUH was adjusted to achieve the
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therapeutic activated partial thromboplastin time (APTT) established by the hospital
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laboratory within every 4–6 h period. After initial admission, the patients received
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oral rivaroxaban, with a loading dose of 15 mg 12/12 h for 21 days, then 20 mg/day
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for 6 months.
136
During the follow-up visits, all the patients were subjected to a DUS analysis
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with defined protocols that assessed the compressibility of the common femoral vein,
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superficial femoral vein, and popliteal vein. Flow recanalization was evaluated by
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confirming the total venous flow (without residual thrombi and complete venous flow
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inside the vessel), the partial venous flow (residual thrombi and partial venous flow
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inside the vessel) or the absence of vein flow. All vessels evaluated were tested for the
142
absence or presence of reflux and the grade of reflux. The clot length was measured
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using proper caliper and measure methods on the DUS. The clot length inside the
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femoral and popliteal vein was defined in 4 aspects: absent; higher than 50% of the
145
total length, lower than 50% of the total vein length and total length of the vein. In
146
order to allow the logistic regression analysis, we have performed a subanalysis where
147
we have chosen to condense femoropliteal clot length in one variable, defined as two
148
dichotomous variables: total vein length or higher than 50% of the total length versus
149
absent or lower than 50% of the total vein length.
6
150
The following ultrasound criteria were used to determine absence of
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recanalization flow: partial compressibility of the vein, diminution of the vessel
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diameter, heterogeneous and hyperechoic thrombus, multiple channels of flow inside
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the veins, reflux, and collateral circulation.5
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All the patients were followed-up with outpatient visits at 1, 3, 6, and 12
155
months after discharge. The following information was recorded at each visit:
156
physical examination, DUS and laboratory tests, such as D-dimer, for all patients.
157
The purpose of this study was to examine the outcomes (after 12 months) in
158
patients after treatment for DVT with Rivaroxaban, by evaluating the DUS-detected
159
recanalization rates and the ultrasound aspects of the recanalization, such as time to
160
appearance of the first signs of recanalization, length of cloth disease and possible
161
reflux in the veins. The PTS diagnosis and prevalence was a secondary outcome.
162
A diagnosis of PTS was made with the Villalta scale when the patient’s
163
symptoms had remained unresolved for 6 months after treatment. Each of the scale’s
164
components (5 symptoms and 6 signs) were rated on a 4-point severity scale, and the
165
points were summed to produce a total score. A score >4 indicated PTS. The severity
166
of each symptom and sign was rated as 0 (absent), 1 (mild), 2 (moderate), or 3
167
(severe). These were summed to yield the total Villalta PTS score: 0 to 4, no PTS; 5
168
to 9, mild PTS; 10 to14, moderate PTS; >15 or presence of an ulcer, severe PTS.
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The statistical analyses were performed with SPSS 15.0 for Windows® (SPSS
170
Inc., Chicago, IL), as percentages of patients and descriptive statistics.. Logistic
171
regressions were used in the univariate and multivariable analyses, and the results are
172
reported as adjusted Odds ratios (ORs) with the accompanying 95% confidence
173
intervals (CIs). ANOVA and a post hoc test were used in the analysis of groups. In all
174
analyses, p values of < 0.05 were considered statistically significant.
7
175
Results
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Fifty-one patients with DVT were admitted to our Vascular Surgery
177
Department and were treated with rivaroxaban. The follow-up period was 360 days.
178
The analyses were performed at 180 days and 360 days.
179
The general characteristics of the patients are shown in Table 1. There was a
180
higher prevalence of provoked DVT (56.5%), which was mainly attributable to
181
previous surgery (28.2%). Among the patients with unprovoked DVT, there were two
182
cases of thrombophilia diagnosed during follow-up, one case of homozygous Leiden
183
V factor deficiency and one case of prothrombin gene mutation.
184
Most patients presented with pain in the affected limb (71.7%), and edema
185
(95.7%). There was a higher incidence of DVT in the left limb (60.9%). Most patients
186
in the whole cohort presented with femoropopliteal DVT (76.1%). These data are
187
summarized in Table 2.
188
The DUS performed at admission showed an absence venous flow in 47
189
patients (93.5%). In contrast, DUS at 360 days showed significant improvement in
190
venous flow, with total patency in 39 patients (76.4%). During follow-up, the
191
incidence of popliteal vein reflux was 21.7% in the total cohort at 360 days..
192
Regarding the average time to appear the first signs of venous flow, the partial and
193
total recanalization rates at admission, 1,3, 6 months and 360 days are summarized in
194
Table 3.
195
Another ultrasound aspect evaluated was the length of the clot thrombus in the
196
femoral and popliteal vein. At the first month 11 patients (21.7%) continued with total
197
occlusion of the vein, with 4 patients (6.5%) with no residual thrombi, with the mean
198
femoral length clot of 16.24cm and mean popliteal length clot 10.67cm. However, at
199
6 months only 2 patients (2.2%) continued with total occlusion of the vein, with 26
8
200
patients (47.8%) with no residual thrombi, with the mean femoral length clot in the
201
femoral vein 1,74cm and the popliteal vein 3.28cm . At 12 months, there were 39
202
patients (76.4%) with no residual thrombi, with the mean length clot in the femoral
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vein of 1.50cm and within the popliteal vein 1.76cm. These datas are summarized on
204
table 4.
205
Univariate and multivariable logistic regression identified the following
206
factors related to total venous recanalization: the absence of popliteal vein reflux (p =
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0.007; OR = 0.386) no residual thrombi (p = 0.008; OR = 3.213), femoropopliteal clot
208
length at 1 month ( p = 0.016; OR = 3.021), femoropopliteal clot length at 6 months
209
(OR = 2.234, p = 0.008). (Table 5).
210
The rate of total venous recanalization at 360 days was 76.4% (39 patients).
211
The incidence of partial venous recanalization was 21.7% (13 patients). Among these
212
patients, 1 patient had 23cm of clot length in the femoral vein, 3 patients 10cm of clot
213
lengh in the femoral vein and 9 patients 5cm of clot length in the femoral vein at
214
admission, however at 12 months, on the other hand , 11 patients had 5cm of clot
215
length in the femoral vein and 2 patients with 3cm of clot length in the popliteal vein.
216
At the first month, 10 patients had a femoral clot length > 10cm, 3 patients a femoral
217
clot length < 10cm, 10 patients a popliteal clot lengh > 7cm, and 3 patients a popliteal
218
clot length < 7cm. The chi-square test showed a statistical significance in the popliteal
219
clot length > 7cm at 1 month and partial recanalization ( p = 0.031) and a statistical
220
significance in the femoral clot length > 10cm at 1 month and partial recanalization
221
rates ( p = 0.028). Therefore, there was an association among popliteal clot lengh >
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7cm and Femoral clot > 10 cm with partial recanalization. There were no cases of
223
nonvenous recanalization in the total cohort.
9
224
The incidence of PTS at 12 months among the patients in this present cohort
225
was 8.3% (4 patients). Regarding the Villalta Score among the patients with PTS two
226
patients had mild PTS (5-9) and two patients moderate PTS (10-14).
227 228 229
Discussion In this cohort, there was evaluated a group of patients diagnosed with DVT
230
and administered Rivaroxaban. The patients who received oral rivaroxaban showed a
231
high total vein recanalization rate within 12 months and earlier appearance of the first
232
signs of vein recanalization. It is important to note that upon admission, ultrasound
233
findings for venous flow showed 93.5% of occlusion. However, when DUS was
234
performed 360 days after treatment there was an improvement in venous flow, with
235
satisfactory recanalization rates. Moreover, regarding the first month of evaluation,
236
the partial and total recanalization rates were improved. In this present study, we have
237
found an association among popliteal clot lengh > 7cm and Femoral clot > 10 cm with
238
partial recanalization. Previous studies have suggested that providing anticoagulation
239
at an appropriate intensity (and duration), particularly during the first week of DVT, is
240
an important way of preventing post-thrombotic Syndrome (PTS).6 Rivaroxaban is a
241
direct-acting oral anticoagulant that induces the rapid onset of anticoagulation and has
242
a predictable pharmacological profile, which allow it to circumvent the early
243
subtherapeutic anticoagulation frequently observed in patients treated with warfarin.
244
Another possible explanation of the better recanalization rates and the incidence of
245
PTS in the rivaroxaban group was reported by Sychev et al.,8 in a Russian study in
246
which they evaluated the correlation between CYP3A family activity and the safety
247
and efficacy of anticoagulant rivaroxaban therapy in patients with DVT. Rivaroxaban
248
is metabolized in the liver by CYP3A4, a cytochrome involved in the metabolism of
10
249
nearly 50% of all medications. These researchers found a statistically significant
250
direct correlation between CYP3A4 activity and both peak and mean rivaroxaban
251
levels. A correlation was also detected between the initial clot length and the time to
252
full recanalization (p < 0.0001). Therefore, they suggested a direct link between the
253
initial clot length and the time to full recanalization. These findings are similar with
254
those found in this present study, whereas the chi-square test showed a statistical
255
significance in the popliteal clot length > 7cm at 1 month and partial recanalization ( p
256
= 0.031) and a statistical significance in the femoral clot length > 10cm and partial
257
recanalization rates ( p = 0.028).
258
Another finding in this cohort is that an univariate and multivariable logistic
259
regression identified the following factors related to total venous recanalization: the
260
absence of popliteal vein reflux (p = 0.007; OR = 0.386) and the absence of residual
261
thrombi diagnosed in the DUS. The popliteal vein reflux is related to worsening
262
venous flow, once the reflux may be caused by residual thrombi that leads to valve
263
insufficiency and scar tissues along the vessel wall. According to Singh et al,9 in a
264
study that compared the development of reflux, recanalization, and clinical outcomes
265
of patients with femoropopliteal and iliofemoral deep venous thrombosis, their
266
emphasis was placed on the relationship between early lysis of clot through
267
thrombolysis and the development of reflux and post-thrombotic syndrome for
268
iliofemoral patients. They concluded that the presence of both residual obstruction
269
and reflux, rather than either one alone, significantly increases the chances for
270
development of PTS. Since thrombolytics eliminates at least one of these factors,
271
residual obstruction, it may aid in decreasing development of PTS in the short term.
272
Meissner et al,10 had also conducted a study where they evaluated the relationship
273
between the presenting features of an acute deep venous thrombosis, the subsequent
11
274
natural history of the thrombus, and the ultimate outcome as defined according to the
275
Society for Vascular Surgery and the North American Chapter of the International
276
Society for Cardiovascular Surgery reporting standards in venous disease. They
277
showed in an univariate analysis that chronic venous disease (CVD) classification
278
was correlated with the reflux score (P =.003), but not with the initial or final
279
thrombus score or with the rate of recanalization or rethrombosis. In a multivariable
280
model of features documented at presentation, only the tibial thrombosis score was a
281
significant predictor of CVD classification (R2 =.06). Outcome was better predicted
282
(R2 =.29) with a model that included variables defined during follow-up the final
283
reflux score, the final popliteal score, and the rate of recanalization. They concluded
284
that the extension of reflux, the presence of persistent popliteal obstruction, and the
285
rate of recanalization are related to ultimate CVD classification, but other
286
determinants remain to be identified. Those findings are similar to those found in this
287
cohort, where popliteal reflux was related to worse outcomes and poor recanalization
288
rates.
289
Another ultrasound aspect evaluated in this cohort was the length of the clot
290
thrombus in the femoral and popliteal vein. After 1 month the recanalization rates was
291
6,5% and at 12 months the rates was 76,4%. However, at 6 months the total vein
292
occlusion has decreased to 2.2% of patients and At 12 months there was no residual
293
thrombi in the veins evaluated. On the other hand, Univariate and multivariable
294
logistic regression identified the following factors related to total venous
295
recanalization: the absence of popliteal vein reflux (p = 0.007; OR = 0.386) no
296
residual thrombi (p = 0.008; OR = 3.213), femoropopliteal clot length at 1 month ( p =
297
0.016; OR = 3.021), femoropopliteal clot length at 6 months (OR = 2.234, p = 0.008).
298
. It is important to notice that the femoral and popliteal clot length reduction at 1
12
299
month was related to better recanalization rates, showing that patients who do not
300
develop recanalization in the first month will have a worse recanalization rates and
301
venous flow. Antignani et al11 evaluated clinically and by means of Echo color
302
Duplex, the fibrinolytic effect of rivaroxaban in patients with recent and previous
303
DVT. They have found that all patients exhibited the complete recanalization of the
304
popliteal veins after 4 weeks of rivaroxaban therapy. Their study suggested that
305
rivaroxaban could have a pro-fibrinolytic effect not only on recent thrombus but also
306
on organized thrombus that results in a complete recanalization of affected veins. It is
307
proposed that this lytic effect will preserve venous valve structure and lead to a
308
reduction of incidence of post-thrombotic syndrome in rivaroxaban treated patients.
309
Those findings are similar to those ones found in this present cohort, whereas patients
310
with Rivaroxaban therapy had a satisfactory vein recanalization rates and faster
311
reduction of the clot length.
312
De Athayde Soares et al12, in a recent publication found that patients who
313
received oral rivaroxaban displayed a lower incidence of postthrombotic syndrome
314
and a better total vein recanalization rate after 6 and 12 months than patients who
315
received warfarin. The PTS in the Rivaroxaban group was 8.7% versus 28.9% in the
316
Warfarin group ( p < 0.001). The rate of total venous recanalization at 360 days was
317
48.8% in the total cohort, but was significantly higher in group 1 (35 patients, 78.3%)
318
than in group 2 (5 patients, 13.2%; P < .001). These findings are properly confirmed
319
in this small prospective cohort, whereas the total vein recanalization rate was 76.4%
320
and the incidence of PTS was 8.3%.
321
A possible explanation for better clot degradability in patients submitted to
322
treatment for DVT with Rivaroxaban can be found in the paper by Varin et al13, where
323
the authors have showed that Rivaroxaban added to plasma or whole blood before
13
324
clotting, in reducing thrombin generation, led to the formation of a looser clot that is
325
more degradable by fibrinolytic enzymes. Permeability and degradability of whole
326
blood clots formed in the presence of rivaroxaban were very similar to those of
327
plasma clots. They concluded that the resistance to fibrinolysis of whole blood clots
328
was reduced considerably when clots were formed with rivaroxaban. Another paper
329
by Undas et al14, showed that rivaroxaban, a direct activated FX (FXa) inhibitor,
330
favorably alters fibrin clot properties. through the formation of fibrin networks
331
composed of thicker fibers forming larger pores associated with a 2-fold increased
332
clot permeability and 3-fold faster lysis has been observed compared with the control
333
clots generated in the absence of rivaroxaban. According to the authors, Rivaroxaban
334
treatment improved fibrin clot properties also in carriers of the G20210A prothrombin
335
mutation (3% of the European population) associated with 30% higher prothrombin
336
levels, but anticoagulant therapy with rivaroxaban cannot lead to return normal fibrin
337
clot phenotyp. These datas explain the reduction of the amount of thrombus observed
338
in this present cohort, from the mean femoral length clot of 16.24cm and mean
339
popliteal length clot 10.67cm at 1 month to the mean femoral length clot in the
340
femoral vein 1,74cm and the popliteal vein 3.28cm observed at 6 months after
341
treatment with rivaroxaban. These datas are very satisfactory and brings new results
342
regarding the DVT treatment with rivaroxaban, which can lead us to question the real
343
necessity of endovascular interventions in acute DVT, something that the ATTRACT
344
trial15 has already demonstrated the similar results regarding PTS in patients
345
submitted to clinical treatment with oral anticoagulant versus endovascular
346
interventions, with less bleeding complications in the clinical treatment group.
347 348
This was a prospective trial performed at a single center, and provides new perspectives on and results for medical therapies for DVT. This paper has some
14
349
limitations, such as small size of the patient sample, lack of direct comparison among
350
oral anticoagulants and single center experience. Despite the small size of the patient
351
sample, the results are statistically significant and applicable. However, larger,
352
multicenter, prospective studies are required to better analyze these findings and
353
extend them into clinical practice. Comparison studies should be performed, mainly
354
comparing the direct oral anticoagulants, regarding the recanalization rates and post
355
thrombotic syndrome.
356
Conclusion
357
In this study, patients who received oral rivaroxaban displayed satisfactory total vein
358
recanalization rate after 6 months and 12 months. The factors associated with better
359
total recanalization rates were the absence of popliteal vein reflux, absence of residual
360
thrombi in the veins femoropopliteal clot length at 1 month ( p = 0.016; OR = 3.021),
361
femoropopliteal clot length at 6 months (OR = 2.234, p = 0.008). . Moreover, the
362
incidence of PTS at 12 months was 8.3%.
363
Acknowledgments
364
None
365
Declaration of conflicting interests
366
The authors declare that they have no conflicts of interest.
367
Funding
368
None.
369 370 371 372 373
15
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5 - Michiels JJ, Moosdorff W, Maasland H, Michiels JM, Lao MU, Neumann HA et al.
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Duplex ultrasound, clinical score, thrombotic risk, and D-dimer testing for
390
evidence based diagnosis and management of deep vein thrombosis and
391
alternative diagnoses in the primary care setting and outpatient ward. Int Angiol.
392
2014 Feb;33:1-19.
393
6 - Kahn SR, Comerota AJ, Cushman M, Evans NS, Ginsberg JS, Goldenberg NA et
394
al. The post-thrombotic syndrome: evidence-based prevention, diagnosis, and
395
treatment strategies: a scientific statement from the American Heart Association.
396
Circulation. 2014;130:1636-1661.
16
397
7 - Erkens PM, ten Cate H, Buller HR, Prins MH. Benchmark for time in therapeutic
398
range in venous thromboembolism: a systematic review and meta-analysis. PLoS
399
One. 2012;7(9):e42269.
400
8 - Sychev DA, Vardanyan A, Rozhkov A, Hachatryan E, Badanyan A, Smirnov V et
401
al. CYP3A Activity and Rivaroxaban Serum Concentrations in Russian Patients with
402
Deep Vein Thrombosis. Genest tes Mol Biomarkers. 2018 Jan; 22 (1): 51-54.
403
9 - Singh H1, Masuda EM. Comparing short-term outcomes of femoral-popliteal and
404
iliofemoral deep venous thrombosis: early lysis and development of reflux. Ann Vasc
405
Surg. 2005 Jan;19(1):74-9.
406
10 - Meissner MH1, Caps MT, Zierler BK, Polissar N, Bergelin RO, Manzo RA,
407
Strandness DE Jr. Determinants of chronic venous disease after acute deep venous
408
thrombosis. J Vasc Surg. 1998 Nov;28(5):826-33.
409
11 - Antignani PL, Allegra C, Fareed J. Treatment of DVT with rivaroxaban and its
410
potential to prevent the post-thrombotic syndrome. Int Angiol. 2018 Nov 20. doi:
411
10.23736/S0392-9590.18.04031-2.
412
12 - de Athayde Soares R, Matielo MF, Brochado Neto FC, Nogueira MP, Almeida
413
RD, Sacilotto R. Comparison of the recanalization rate and postthrombotic syndrome
414
in patients with deep venous thrombosis treated with rivaroxaban or warfarin.
415
Surgery. 2019 Jul 2. pii: S0039-6060(19)30295-8. doi: 10.1016/j.surg.2019.05.030
416
13 - Varin R, Mirshahi S, Mirshahi P, Klein C, Jamshedov J, Chidiac Jet al. Whole
417
blood clots are more resistant to lysis than plasma clots--greater efficacy of
418
rivaroxaban.
419
10.1016/j.thromres.2012.11.029. Epub 2013 Jan 11.
Thromb
Res.
2013
Mar;131(3):e100-9.
doi:
17
420
14 - Undas A, Zabczyk M. Antithrombotic medications and their impact on fibrin clot
421
structure
422
10.26402/jpp.2018.4.02. Epub 2018 Nov 7.
423
15 - S. Vedantham, S.Z. Goldhaber, J.A. Julian, S.R. Kahn, M.R. Jaff, D.J. Cohen, et
424
al, for the ATTRACT Trial Investigators. Pharmacomechanical Catheter-Directed
425
Thrombolysis for Deep-Vein Thrombosis. N engl j med 377;23
and
function.
J
Physiol
Pharmacol.
2018
Aug;69(4).
doi:
426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444
18
445
Table 1. Clinical characteristics
446 Variable
Rixaroxaban (n =51)
Age, years
54.93 ± 3.08
Females
29 (56.5%)
Hypertension
16 (32.6%)
Diabetes
6 (10.9%)
Heart disease
6 (10.9%)
Tobacco use
6 (10.9%)
Provoked DVT 29 (56.5%)
Trauma
6 (10.9%)
Immobilization 3 (6.5%) Previous surgery
14 (28.2%)
447 448 449
19
450
Table 2. Clinical characteristics upon admission Variable
Rivaroxaban n =51
Wells criteria
3.98 ± 1.95
Pain
37 (71.7%)
Edema
49 (95.7%)
Left limb
31 (60.9%)
Segment affected Femoropopliteal 39 (76.1%) Iliofemoral
12 (23.9%)
D-dimer
50 (97.8%)
positive Symptomatic
0 (0%)
PE1 CVD2
23 (45.7%)
Enoxaparin
45 (89.1%)
UH3
6 (10.9%)
451
1 – pulmonary embolism; 2 – chronic venous disease (varicose veins); 3 -
452
unfractionated heparin
453 454
20
455
Table 3. Ultrasound data on venous flow at admission, 1, 3, 6 months and after 360
456
days Variable
Rivaroxaban n =51
At admission Occlusion
47 (93.5%)
Partial flow
4 (6.5%)
At 1 month Occlusion
11 (21.7%)
Partial flow
36 (71.7%)
Total Flow
4 (6.5%)
At 3 months
Occlusion
2 (2.2%)
Partial flow
36 (71.7%)
Total Flow
13 (26.1%)
At 6 months Occlusion
2 (2.2%)
Partial Flow
23 (45%)
Total Flow
26 (47.8%)
At 360 days Occlusion
0 (0%)
Partial flow
12 (21.7%)
21
Total patency
39 (76.4%)
457 458
22
459
Table 4. Ultrasound data on femoral / popliteal clot length at 1, 6 and 12 months Variable Rivaroxaban Femoral clot Popliteal clot length (mean) N =51 lenght (mean)
At 1 month
At 1 month
Total occlusion
11 (21.7%)
< 50%
16 (31.3%)
> 50%
20 (39.2%)
No thrombi
4 (6.5%)
At 6 months
16.24 ± 4.3
10.67 ± 6.7
At 6 months
Total occlusion
2 (2.2%)
< 50%
20 (39.2%)
> 50%
3 (5.8%)
No thrombi
26 (47.8%)
At 12 months
1.74 ± 0.5
3.28 ± 1.8
At 12 months
Total occlusion
0 (0%)
< 50%
6 (13%)
> 50%
6 (13%)
No thrombi
39 (78.3%)
1.50 ± 0.38
1.76 ± 0.9
460
23
461 462 463 464 465
Table 5. Univariate and multivariable linear regression analyses of factors related to total vein recanalization
B, coefficient; OR, odds ratio; CI, confidence interval.
Variable
Univariate analysis
Multivariate analysis
B
OR
95% CI
P
B
OR
95% CI
P
D-Dimer positive
0.642
0.790
.0788–1.152
.675
0.341
0.561
0.838–3.597
.789
Segment of DVT
0.322
7.768
1.921–11.561
.246
7.895
0.802
1.321–13.194
.466
Obesity
0.812
8.680
0.563-0.821
.442
0.133
6.671
1.541-23.234
.669
Female Gender
0.731
0.785
0.120-0.651
.122
1.811
0.015
0.429-11.330
.249
Femoral vein reflux
1.953
1.731
0.324-2.111
.111
4.243
5.314
0.334-5.433
.123
Popliteal vein reflux
1.953
0.386
0.662-0.811
.007
1.596
0.386
0.662-0.811
.007
Residual thrombi
1.876
3.213
1.324-4.321
.008
1.567
3.213
1.456-3.796
.008
Femoropopliteal clot
0.607
3.021
5.987-22.565
.016
1.657
3.021
5.879-14.234
.016
1.743
2.234
3.484-19.971
.008
1.878
2.234
4.675-8.989
.008
length at 1 month Femoropopliteal clot length at 6 months .
466
24
S0890-5096(20)30037-6
DOI:
https://doi.org/10.1016/j.avsg.2020.01.017
Reference:
AVSG 4872
To appear in:
Annals of Vascular Surgery
Received Date: 16 November 2019 Revised Date:
1 January 2020
Accepted Date: 6 January 2020
Please cite this article as: de Athayde Soares R, Matielo MF, Brochado Neto FC, Almeida RD, Sacilotto R, Ultrasound aspects and Recanalization Rates in Patients with Lower-limb Deep Venous Thrombosis Treated with Rivaroxaban, Annals of Vascular Surgery (2020), doi: https://doi.org/10.1016/ j.avsg.2020.01.017. 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
Clinical Research
2
Ultrasound aspects and Recanalization Rates in Patients with Lower-limb Deep
3
Venous Thrombosis Treated with Rivaroxaban
4
Rafael de Athayde Soares, M.D. Hospital do Servidor Público Estadual de São Paulo
5
Email: [email protected] Phone: +5511999813931
6
(Corresponding Author)
7
Marcelo Fernando Matielo, PhD, Hospital do Servidor Público Estadual de São Paulo
8
Francisco Cardoso Brochado Neto, PhD, Hospital do Servidor Público Estadual de
9
São Paulo.
10
Rogério Duque Almeida, M.D, Hospital do Servidor Público Estadual de São Paulo
11
Roberto Sacilotto, PhD, Hospital do Servidor Público Estadual de São Paulo
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
1
29
Abstract
30
OBJECTIVES In this paper, we report the Ultrasound aspects and Recanalization
31
Rates of patients with deep venous thrombosis (DVT) in the lower limbs treated with
32
the rivaroxaban, focusing on the recanalization rate and the ultrassonographic aspects.
33
METHODS This was a prospective, consecutive cohort study of patients admitted
34
with DVT who were submitted to treatment with Rivaroxaban for 6 months to the
35
Division of Vascular and Endovascular Surgery, Hospital do Servidor Público
36
Estadual, São Paulo, Brazil, between march 2016 and July 2018.
37
RESULTS Fifty-one patients with DVT were admitted to the Vascular Surgery
38
Department and received Rivaroxaban for 6 months. The follow-up time was 360
39
days. Analyses were performed at 180 and 360 days. The rate of total venous
40
recanalization at 360 days was 76.4% (39 patients). The incidence of partial venous
41
recanalization was 23.5% (12 patients). At the first month, 11 patients (21.7%)
42
continued with total occlusion of the vein, with 4 patients (6.5%) with no residual
43
thrombi. However, at 6 months only 2 patients (2.2%) continued with total occlusion
44
of the vein, with 26 patients (47.8%) with no residual thrombi. At 12 months, there
45
were 39 patients (76.4%) with no residual thrombi. Univariate and multivariable
46
logistic regression identified the following factors related to total venous
47
recanalization: the absence of popliteal vein reflux (p = 0.007; OR = 0.386), no
48
residual thrombi (p = 0.008; OR = 3.213), femoropopliteal clot length at 1 month ( p =
49
0.016; OR = 3.021), femoropopliteal clot length at 6 months (OR = 2.234, p = 0.008),.
50
The incidence of PTS at 12 months was 8.3%.
51 52
CONCLUSIONS In this study, patients who received oral rivaroxaban displayed
53
satisfatory total vein recanalization rate after 6 months and 12 months. The factors
2
54
associated with better total recanalization rates were the absence of popliteal vein
55
reflux, absence of residual thrombi in the veins, femoropopliteal clot length at 1
56
month ( p = 0.016; OR = 3.021), femoropopliteal clot length at 6 months (OR = 2.234,
57
p = 0.008). Moreover, the incidence of PTS at 12 months was 8.3%.
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
3
76 77
Introduction The treatment for Deep venous thrombosis (DVT) has developed substantially
78
during the last years, mainly due to the new anticoagulation drugs available for the
79
treatment of this common and dreadful condition. Since the publication of the
80
EINSTEIN Clinical Trial Program,1 rivaroxaban has shown to be at least as effective
81
as enoxaparin/vitamin K antagonist in the acute treatment and secondary prevention
82
of recurrent venous thromboembolism in patients with creatinine clearance > 30
83
mL/min.1,2
84
The ultrasound aspects of the evolution of the DVT plays an important role in
85
the prognostic factors related to the outcomes of this disease. According to Dronkers
86
et al,3 two ultrasonographic parameters measured during or after the treatment of
87
DVT in the leg predicted post thrombotic syndrome (PTS): residual vein thrombosis
88
(pooled OR, 2.17) and venous reflux at the popliteal level (pooled OR, 1.34). These
89
ultrassonographic findings correlates with important clinical prognostic of the DVT,
90
mainly due to the high risk of the development of PTS, a condition related to poorer
91
clinical evolution of the patients. Another study by Jeraj et al4 suggested that patients
92
with residual thrombi were at greater risk of PTS than patients with total vein
93
recanalization (OR, 6.0; p = 0.006). No difference in the presence of femoral neither
94
popliteal reflux was observed in these patients.
95
There are few studies in the literature telling about the new anticoagulation
96
drugs for treatment of DVT and the recanalization rates or ultrasound aspects of this
97
treatment. Therefore, the objective of this study was to evaluate the recanalization rate
98
measured with duplex ultrasound (DUS) and the ultrasound aspects in patients
99
suffering from DVT who were treated with oral rivaroxaban.
100
4
101
Methods
102
This study was approved by the Research Ethics Committee of the Hospital do
103
Servidor Público Estadual, São Paulo, Brazil. This prospective, consecutive, cohort
104
study included patients treated for acute iliofemoral and/or femoropopliteal DVT of a
105
lower limb at the Division of Vascular and Endovascular Surgery, Hospital do
106
Servidor Público Estadual, São Paulo, Brazil, between march 2016 and July 2018.
107
Patient informed consent was obtained for the study, according to the principles
108
outlines in the Declaration to Helsink. The patient data were collected during an
109
appointment at the routine follow-up, and recorded with the proper protocols. The
110
data obtained included the patient’s general and demographic characteristics, and the
111
information recorded during the outpatient follow-up visits. This research received no
112
specific funding.
113
The non-inclusion criteria were: pregnancy, age < 18 years or > 80 years,
114
chronic renal failure, chronic hepatic failure, inferior vena cava thrombosis,
115
contraindication for any type of anticoagulation, previous DVT on the ipsilateral
116
affected limb, or any type of active cancer, patients who refused to participate in the
117
study.
118
The exclusion criteria were pre-defined prior to the start of the study and were
119
defined as: several hemorrhagic complications that required the discontinuation of
120
anticoagulation, death after < 30 days, allergic reaction to any anticoagulant, a
121
diagnosis of active cancer during follow-up, loss to follow-up.
122
The diagnosis of DVT was made with clinical signs and symptoms, laboratory
123
tests such as D-dimer, and routine DUS of the affected limb. The criteria used to
124
confirm acute DVT with DUS were the absence or diminution of venous flow,
125
incompressibility of the vessel, visible thrombus, enlarged vein diameter, immobility
5
126
of the valves, and loss of respiratory phasicity.5 All DUS were performed by a single
127
examination, vascular surgeon, blinded physician.
128
All the patients diagnosed with acute DVT were hospitalized and received
129
initial anticoagulation with subcutaneous enoxaparin (1 mg/kg/dose) every 12 h
130
(12/12 h) or intravenous unfractionated heparin (IUH) (loading dose 80 UI/kg, and 18
131
UI/kg/h) for at least 48–72 h. The infusion dose of IUH was adjusted to achieve the
132
therapeutic activated partial thromboplastin time (APTT) established by the hospital
133
laboratory within every 4–6 h period. After initial admission, the patients received
134
oral rivaroxaban, with a loading dose of 15 mg 12/12 h for 21 days, then 20 mg/day
135
for 6 months.
136
During the follow-up visits, all the patients were subjected to a DUS analysis
137
with defined protocols that assessed the compressibility of the common femoral vein,
138
superficial femoral vein, and popliteal vein. Flow recanalization was evaluated by
139
confirming the total venous flow (without residual thrombi and complete venous flow
140
inside the vessel), the partial venous flow (residual thrombi and partial venous flow
141
inside the vessel) or the absence of vein flow. All vessels evaluated were tested for the
142
absence or presence of reflux and the grade of reflux. The clot length was measured
143
using proper caliper and measure methods on the DUS. The clot length inside the
144
femoral and popliteal vein was defined in 4 aspects: absent; higher than 50% of the
145
total length, lower than 50% of the total vein length and total length of the vein. In
146
order to allow the logistic regression analysis, we have performed a subanalysis where
147
we have chosen to condense femoropliteal clot length in one variable, defined as two
148
dichotomous variables: total vein length or higher than 50% of the total length versus
149
absent or lower than 50% of the total vein length.
6
150
The following ultrasound criteria were used to determine absence of
151
recanalization flow: partial compressibility of the vein, diminution of the vessel
152
diameter, heterogeneous and hyperechoic thrombus, multiple channels of flow inside
153
the veins, reflux, and collateral circulation.5
154
All the patients were followed-up with outpatient visits at 1, 3, 6, and 12
155
months after discharge. The following information was recorded at each visit:
156
physical examination, DUS and laboratory tests, such as D-dimer, for all patients.
157
The purpose of this study was to examine the outcomes (after 12 months) in
158
patients after treatment for DVT with Rivaroxaban, by evaluating the DUS-detected
159
recanalization rates and the ultrasound aspects of the recanalization, such as time to
160
appearance of the first signs of recanalization, length of cloth disease and possible
161
reflux in the veins. The PTS diagnosis and prevalence was a secondary outcome.
162
A diagnosis of PTS was made with the Villalta scale when the patient’s
163
symptoms had remained unresolved for 6 months after treatment. Each of the scale’s
164
components (5 symptoms and 6 signs) were rated on a 4-point severity scale, and the
165
points were summed to produce a total score. A score >4 indicated PTS. The severity
166
of each symptom and sign was rated as 0 (absent), 1 (mild), 2 (moderate), or 3
167
(severe). These were summed to yield the total Villalta PTS score: 0 to 4, no PTS; 5
168
to 9, mild PTS; 10 to14, moderate PTS; >15 or presence of an ulcer, severe PTS.
169
The statistical analyses were performed with SPSS 15.0 for Windows® (SPSS
170
Inc., Chicago, IL), as percentages of patients and descriptive statistics.. Logistic
171
regressions were used in the univariate and multivariable analyses, and the results are
172
reported as adjusted Odds ratios (ORs) with the accompanying 95% confidence
173
intervals (CIs). ANOVA and a post hoc test were used in the analysis of groups. In all
174
analyses, p values of < 0.05 were considered statistically significant.
7
175
Results
176
Fifty-one patients with DVT were admitted to our Vascular Surgery
177
Department and were treated with rivaroxaban. The follow-up period was 360 days.
178
The analyses were performed at 180 days and 360 days.
179
The general characteristics of the patients are shown in Table 1. There was a
180
higher prevalence of provoked DVT (56.5%), which was mainly attributable to
181
previous surgery (28.2%). Among the patients with unprovoked DVT, there were two
182
cases of thrombophilia diagnosed during follow-up, one case of homozygous Leiden
183
V factor deficiency and one case of prothrombin gene mutation.
184
Most patients presented with pain in the affected limb (71.7%), and edema
185
(95.7%). There was a higher incidence of DVT in the left limb (60.9%). Most patients
186
in the whole cohort presented with femoropopliteal DVT (76.1%). These data are
187
summarized in Table 2.
188
The DUS performed at admission showed an absence venous flow in 47
189
patients (93.5%). In contrast, DUS at 360 days showed significant improvement in
190
venous flow, with total patency in 39 patients (76.4%). During follow-up, the
191
incidence of popliteal vein reflux was 21.7% in the total cohort at 360 days..
192
Regarding the average time to appear the first signs of venous flow, the partial and
193
total recanalization rates at admission, 1,3, 6 months and 360 days are summarized in
194
Table 3.
195
Another ultrasound aspect evaluated was the length of the clot thrombus in the
196
femoral and popliteal vein. At the first month 11 patients (21.7%) continued with total
197
occlusion of the vein, with 4 patients (6.5%) with no residual thrombi, with the mean
198
femoral length clot of 16.24cm and mean popliteal length clot 10.67cm. However, at
199
6 months only 2 patients (2.2%) continued with total occlusion of the vein, with 26
8
200
patients (47.8%) with no residual thrombi, with the mean femoral length clot in the
201
femoral vein 1,74cm and the popliteal vein 3.28cm . At 12 months, there were 39
202
patients (76.4%) with no residual thrombi, with the mean length clot in the femoral
203
vein of 1.50cm and within the popliteal vein 1.76cm. These datas are summarized on
204
table 4.
205
Univariate and multivariable logistic regression identified the following
206
factors related to total venous recanalization: the absence of popliteal vein reflux (p =
207
0.007; OR = 0.386) no residual thrombi (p = 0.008; OR = 3.213), femoropopliteal clot
208
length at 1 month ( p = 0.016; OR = 3.021), femoropopliteal clot length at 6 months
209
(OR = 2.234, p = 0.008). (Table 5).
210
The rate of total venous recanalization at 360 days was 76.4% (39 patients).
211
The incidence of partial venous recanalization was 21.7% (13 patients). Among these
212
patients, 1 patient had 23cm of clot length in the femoral vein, 3 patients 10cm of clot
213
lengh in the femoral vein and 9 patients 5cm of clot length in the femoral vein at
214
admission, however at 12 months, on the other hand , 11 patients had 5cm of clot
215
length in the femoral vein and 2 patients with 3cm of clot length in the popliteal vein.
216
At the first month, 10 patients had a femoral clot length > 10cm, 3 patients a femoral
217
clot length < 10cm, 10 patients a popliteal clot lengh > 7cm, and 3 patients a popliteal
218
clot length < 7cm. The chi-square test showed a statistical significance in the popliteal
219
clot length > 7cm at 1 month and partial recanalization ( p = 0.031) and a statistical
220
significance in the femoral clot length > 10cm at 1 month and partial recanalization
221
rates ( p = 0.028). Therefore, there was an association among popliteal clot lengh >
222
7cm and Femoral clot > 10 cm with partial recanalization. There were no cases of
223
nonvenous recanalization in the total cohort.
9
224
The incidence of PTS at 12 months among the patients in this present cohort
225
was 8.3% (4 patients). Regarding the Villalta Score among the patients with PTS two
226
patients had mild PTS (5-9) and two patients moderate PTS (10-14).
227 228 229
Discussion In this cohort, there was evaluated a group of patients diagnosed with DVT
230
and administered Rivaroxaban. The patients who received oral rivaroxaban showed a
231
high total vein recanalization rate within 12 months and earlier appearance of the first
232
signs of vein recanalization. It is important to note that upon admission, ultrasound
233
findings for venous flow showed 93.5% of occlusion. However, when DUS was
234
performed 360 days after treatment there was an improvement in venous flow, with
235
satisfactory recanalization rates. Moreover, regarding the first month of evaluation,
236
the partial and total recanalization rates were improved. In this present study, we have
237
found an association among popliteal clot lengh > 7cm and Femoral clot > 10 cm with
238
partial recanalization. Previous studies have suggested that providing anticoagulation
239
at an appropriate intensity (and duration), particularly during the first week of DVT, is
240
an important way of preventing post-thrombotic Syndrome (PTS).6 Rivaroxaban is a
241
direct-acting oral anticoagulant that induces the rapid onset of anticoagulation and has
242
a predictable pharmacological profile, which allow it to circumvent the early
243
subtherapeutic anticoagulation frequently observed in patients treated with warfarin.
244
Another possible explanation of the better recanalization rates and the incidence of
245
PTS in the rivaroxaban group was reported by Sychev et al.,8 in a Russian study in
246
which they evaluated the correlation between CYP3A family activity and the safety
247
and efficacy of anticoagulant rivaroxaban therapy in patients with DVT. Rivaroxaban
248
is metabolized in the liver by CYP3A4, a cytochrome involved in the metabolism of
10
249
nearly 50% of all medications. These researchers found a statistically significant
250
direct correlation between CYP3A4 activity and both peak and mean rivaroxaban
251
levels. A correlation was also detected between the initial clot length and the time to
252
full recanalization (p < 0.0001). Therefore, they suggested a direct link between the
253
initial clot length and the time to full recanalization. These findings are similar with
254
those found in this present study, whereas the chi-square test showed a statistical
255
significance in the popliteal clot length > 7cm at 1 month and partial recanalization ( p
256
= 0.031) and a statistical significance in the femoral clot length > 10cm and partial
257
recanalization rates ( p = 0.028).
258
Another finding in this cohort is that an univariate and multivariable logistic
259
regression identified the following factors related to total venous recanalization: the
260
absence of popliteal vein reflux (p = 0.007; OR = 0.386) and the absence of residual
261
thrombi diagnosed in the DUS. The popliteal vein reflux is related to worsening
262
venous flow, once the reflux may be caused by residual thrombi that leads to valve
263
insufficiency and scar tissues along the vessel wall. According to Singh et al,9 in a
264
study that compared the development of reflux, recanalization, and clinical outcomes
265
of patients with femoropopliteal and iliofemoral deep venous thrombosis, their
266
emphasis was placed on the relationship between early lysis of clot through
267
thrombolysis and the development of reflux and post-thrombotic syndrome for
268
iliofemoral patients. They concluded that the presence of both residual obstruction
269
and reflux, rather than either one alone, significantly increases the chances for
270
development of PTS. Since thrombolytics eliminates at least one of these factors,
271
residual obstruction, it may aid in decreasing development of PTS in the short term.
272
Meissner et al,10 had also conducted a study where they evaluated the relationship
273
between the presenting features of an acute deep venous thrombosis, the subsequent
11
274
natural history of the thrombus, and the ultimate outcome as defined according to the
275
Society for Vascular Surgery and the North American Chapter of the International
276
Society for Cardiovascular Surgery reporting standards in venous disease. They
277
showed in an univariate analysis that chronic venous disease (CVD) classification
278
was correlated with the reflux score (P =.003), but not with the initial or final
279
thrombus score or with the rate of recanalization or rethrombosis. In a multivariable
280
model of features documented at presentation, only the tibial thrombosis score was a
281
significant predictor of CVD classification (R2 =.06). Outcome was better predicted
282
(R2 =.29) with a model that included variables defined during follow-up the final
283
reflux score, the final popliteal score, and the rate of recanalization. They concluded
284
that the extension of reflux, the presence of persistent popliteal obstruction, and the
285
rate of recanalization are related to ultimate CVD classification, but other
286
determinants remain to be identified. Those findings are similar to those found in this
287
cohort, where popliteal reflux was related to worse outcomes and poor recanalization
288
rates.
289
Another ultrasound aspect evaluated in this cohort was the length of the clot
290
thrombus in the femoral and popliteal vein. After 1 month the recanalization rates was
291
6,5% and at 12 months the rates was 76,4%. However, at 6 months the total vein
292
occlusion has decreased to 2.2% of patients and At 12 months there was no residual
293
thrombi in the veins evaluated. On the other hand, Univariate and multivariable
294
logistic regression identified the following factors related to total venous
295
recanalization: the absence of popliteal vein reflux (p = 0.007; OR = 0.386) no
296
residual thrombi (p = 0.008; OR = 3.213), femoropopliteal clot length at 1 month ( p =
297
0.016; OR = 3.021), femoropopliteal clot length at 6 months (OR = 2.234, p = 0.008).
298
. It is important to notice that the femoral and popliteal clot length reduction at 1
12
299
month was related to better recanalization rates, showing that patients who do not
300
develop recanalization in the first month will have a worse recanalization rates and
301
venous flow. Antignani et al11 evaluated clinically and by means of Echo color
302
Duplex, the fibrinolytic effect of rivaroxaban in patients with recent and previous
303
DVT. They have found that all patients exhibited the complete recanalization of the
304
popliteal veins after 4 weeks of rivaroxaban therapy. Their study suggested that
305
rivaroxaban could have a pro-fibrinolytic effect not only on recent thrombus but also
306
on organized thrombus that results in a complete recanalization of affected veins. It is
307
proposed that this lytic effect will preserve venous valve structure and lead to a
308
reduction of incidence of post-thrombotic syndrome in rivaroxaban treated patients.
309
Those findings are similar to those ones found in this present cohort, whereas patients
310
with Rivaroxaban therapy had a satisfactory vein recanalization rates and faster
311
reduction of the clot length.
312
De Athayde Soares et al12, in a recent publication found that patients who
313
received oral rivaroxaban displayed a lower incidence of postthrombotic syndrome
314
and a better total vein recanalization rate after 6 and 12 months than patients who
315
received warfarin. The PTS in the Rivaroxaban group was 8.7% versus 28.9% in the
316
Warfarin group ( p < 0.001). The rate of total venous recanalization at 360 days was
317
48.8% in the total cohort, but was significantly higher in group 1 (35 patients, 78.3%)
318
than in group 2 (5 patients, 13.2%; P < .001). These findings are properly confirmed
319
in this small prospective cohort, whereas the total vein recanalization rate was 76.4%
320
and the incidence of PTS was 8.3%.
321
A possible explanation for better clot degradability in patients submitted to
322
treatment for DVT with Rivaroxaban can be found in the paper by Varin et al13, where
323
the authors have showed that Rivaroxaban added to plasma or whole blood before
13
324
clotting, in reducing thrombin generation, led to the formation of a looser clot that is
325
more degradable by fibrinolytic enzymes. Permeability and degradability of whole
326
blood clots formed in the presence of rivaroxaban were very similar to those of
327
plasma clots. They concluded that the resistance to fibrinolysis of whole blood clots
328
was reduced considerably when clots were formed with rivaroxaban. Another paper
329
by Undas et al14, showed that rivaroxaban, a direct activated FX (FXa) inhibitor,
330
favorably alters fibrin clot properties. through the formation of fibrin networks
331
composed of thicker fibers forming larger pores associated with a 2-fold increased
332
clot permeability and 3-fold faster lysis has been observed compared with the control
333
clots generated in the absence of rivaroxaban. According to the authors, Rivaroxaban
334
treatment improved fibrin clot properties also in carriers of the G20210A prothrombin
335
mutation (3% of the European population) associated with 30% higher prothrombin
336
levels, but anticoagulant therapy with rivaroxaban cannot lead to return normal fibrin
337
clot phenotyp. These datas explain the reduction of the amount of thrombus observed
338
in this present cohort, from the mean femoral length clot of 16.24cm and mean
339
popliteal length clot 10.67cm at 1 month to the mean femoral length clot in the
340
femoral vein 1,74cm and the popliteal vein 3.28cm observed at 6 months after
341
treatment with rivaroxaban. These datas are very satisfactory and brings new results
342
regarding the DVT treatment with rivaroxaban, which can lead us to question the real
343
necessity of endovascular interventions in acute DVT, something that the ATTRACT
344
trial15 has already demonstrated the similar results regarding PTS in patients
345
submitted to clinical treatment with oral anticoagulant versus endovascular
346
interventions, with less bleeding complications in the clinical treatment group.
347 348
This was a prospective trial performed at a single center, and provides new perspectives on and results for medical therapies for DVT. This paper has some
14
349
limitations, such as small size of the patient sample, lack of direct comparison among
350
oral anticoagulants and single center experience. Despite the small size of the patient
351
sample, the results are statistically significant and applicable. However, larger,
352
multicenter, prospective studies are required to better analyze these findings and
353
extend them into clinical practice. Comparison studies should be performed, mainly
354
comparing the direct oral anticoagulants, regarding the recanalization rates and post
355
thrombotic syndrome.
356
Conclusion
357
In this study, patients who received oral rivaroxaban displayed satisfactory total vein
358
recanalization rate after 6 months and 12 months. The factors associated with better
359
total recanalization rates were the absence of popliteal vein reflux, absence of residual
360
thrombi in the veins femoropopliteal clot length at 1 month ( p = 0.016; OR = 3.021),
361
femoropopliteal clot length at 6 months (OR = 2.234, p = 0.008). . Moreover, the
362
incidence of PTS at 12 months was 8.3%.
363
Acknowledgments
364
None
365
Declaration of conflicting interests
366
The authors declare that they have no conflicts of interest.
367
Funding
368
None.
369 370 371 372 373
15
374
References
375
1 – –Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS et
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al. Oral rivaroxaban for symptomatic venous thromboembolism.N Engl J Med.
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445
Table 1. Clinical characteristics
446 Variable
Rixaroxaban (n =51)
Age, years
54.93 ± 3.08
Females
29 (56.5%)
Hypertension
16 (32.6%)
Diabetes
6 (10.9%)
Heart disease
6 (10.9%)
Tobacco use
6 (10.9%)
Provoked DVT 29 (56.5%)
Trauma
6 (10.9%)
Immobilization 3 (6.5%) Previous surgery
14 (28.2%)
447 448 449
19
450
Table 2. Clinical characteristics upon admission Variable
Rivaroxaban n =51
Wells criteria
3.98 ± 1.95
Pain
37 (71.7%)
Edema
49 (95.7%)
Left limb
31 (60.9%)
Segment affected Femoropopliteal 39 (76.1%) Iliofemoral
12 (23.9%)
D-dimer
50 (97.8%)
positive Symptomatic
0 (0%)
PE1 CVD2
23 (45.7%)
Enoxaparin
45 (89.1%)
UH3
6 (10.9%)
451
1 – pulmonary embolism; 2 – chronic venous disease (varicose veins); 3 -
452
unfractionated heparin
453 454
20
455
Table 3. Ultrasound data on venous flow at admission, 1, 3, 6 months and after 360
456
days Variable
Rivaroxaban n =51
At admission Occlusion
47 (93.5%)
Partial flow
4 (6.5%)
At 1 month Occlusion
11 (21.7%)
Partial flow
36 (71.7%)
Total Flow
4 (6.5%)
At 3 months
Occlusion
2 (2.2%)
Partial flow
36 (71.7%)
Total Flow
13 (26.1%)
At 6 months Occlusion
2 (2.2%)
Partial Flow
23 (45%)
Total Flow
26 (47.8%)
At 360 days Occlusion
0 (0%)
Partial flow
12 (21.7%)
21
Total patency
39 (76.4%)
457 458
22
459
Table 4. Ultrasound data on femoral / popliteal clot length at 1, 6 and 12 months Variable Rivaroxaban Femoral clot Popliteal clot length (mean) N =51 lenght (mean)
At 1 month
At 1 month
Total occlusion
11 (21.7%)
< 50%
16 (31.3%)
> 50%
20 (39.2%)
No thrombi
4 (6.5%)
At 6 months
16.24 ± 4.3
10.67 ± 6.7
At 6 months
Total occlusion
2 (2.2%)
< 50%
20 (39.2%)
> 50%
3 (5.8%)
No thrombi
26 (47.8%)
At 12 months
1.74 ± 0.5
3.28 ± 1.8
At 12 months
Total occlusion
0 (0%)
< 50%
6 (13%)
> 50%
6 (13%)
No thrombi
39 (78.3%)
1.50 ± 0.38
1.76 ± 0.9
460
23
461 462 463 464 465
Table 5. Univariate and multivariable linear regression analyses of factors related to total vein recanalization
B, coefficient; OR, odds ratio; CI, confidence interval.
Variable
Univariate analysis
Multivariate analysis
B
OR
95% CI
P
B
OR
95% CI
P
D-Dimer positive
0.642
0.790
.0788–1.152
.675
0.341
0.561
0.838–3.597
.789
Segment of DVT
0.322
7.768
1.921–11.561
.246
7.895
0.802
1.321–13.194
.466
Obesity
0.812
8.680
0.563-0.821
.442
0.133
6.671
1.541-23.234
.669
Female Gender
0.731
0.785
0.120-0.651
.122
1.811
0.015
0.429-11.330
.249
Femoral vein reflux
1.953
1.731
0.324-2.111
.111
4.243
5.314
0.334-5.433
.123
Popliteal vein reflux
1.953
0.386
0.662-0.811
.007
1.596
0.386
0.662-0.811
.007
Residual thrombi
1.876
3.213
1.324-4.321
.008
1.567
3.213
1.456-3.796
.008
Femoropopliteal clot
0.607
3.021
5.987-22.565
.016
1.657
3.021
5.879-14.234
.016
1.743
2.234
3.484-19.971
.008
1.878
2.234
4.675-8.989
.008
length at 1 month Femoropopliteal clot length at 6 months .
466
24