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Vascular Medicine
2015, Vol. 20(2) 112 –116
© The Author(s) 2014
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DOI: 10.1177/1358863X14553882
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Introduction
Post-thrombotic syndrome (PTS) develops in approxi-
mately 25–60% of patients with acute lower extremity
deep venous thrombosis (DVT) depending on severity,
chronicity, anatomic level of involvement and efficacy
of anticoagulation.1,2 The frequency increases with
occlusive iliac venous thrombosis. PTS results in sig-
nificant morbidity and a staggering toll on health care
resources.3 There is a growing body of evidence dem-
onstrating that thromboreductive strategies including
percutaneous endovenous intervention (PEVI) reduce
this incidence.4–6 The new oral anticoagulants (NOACs)
that have become available over the last few years have
shown promising results in the treatment of DVT.7
Since they can directly and indirectly target clot-bound
thrombin, they may be superior to vitamin K antago-
nists (VKAs). All related studies evaluating these drugs
thus far have excluded patients undergoing catheter-
directed thrombolysis (CDT). It is plausible to
postulate that the synergistic effect of rapid thrombus
reduction by CDT and subsequent treatment with
NOACs can further reduce the PTS rate. The role of
PEVI, which usually involves some form of CDT plus
NOAC in the reduction of PTS, has not been previously
investigated. We thus embarked to evaluate this role in
patients presenting with acute DVT of the lower
extremities.
Low incidence of post-thrombotic syndrome in
patients treated with new oral anticoagulants
and percutaneous endovenous intervention for
lower extremity deep venous thrombosis
Mohsen Sharifi1,2, Wilbur Freeman2, Curt Bay2, Mirali Sharifi1 and
Frederic Schwartz2
Abstract
Post-thrombotic syndrome (PTS) is a common complication of deep venous thrombosis (DVT) of the iliofemoral
venous system leading to significant morbidity and high health care costs. It has been recently shown that
percutaneous endovenous intervention (PEVI) can effectively reduce the incidence of PTS. The role of new oral
anticoagulants (NOACs) in combination with PEVI in the reduction of PTS has not been previously studied.
This report sought to evaluate the role of PEVI plus NOACs in the reduction of PTS in acute symptomatic
femoropopliteal and iliac DVT. We studied 127 patients with acute lower extremity DVT who had undergone
PEVI plus administration of NOACs. All had received a minimum of 3 months of anticoagulation with a NOAC
following PEVI. The mean follow-up was 22±5 months. The patients were evaluated for development of PTS,
bleeding, recurrent venous thromboembolism (VTE), duration of hospitalization and mortality. There was no in-
hospital bleeding. The mean duration of hospitalization was 46±9 hours. DVT occurred in two patients who had
been later switched to warfarin. There were four non-VTE-related deaths. PTS developed in five patients (3%),
two of whom were those who had been switched to warfarin. Their mean Villalta score was 6.2±0.9. We conclude
that the combination of PEVI plus NOAC and low dose aspirin is associated with a very low rate of PTS with the
severity being only mild. This approach leads to very low rates of bleeding and recurrent VTE and promotes early
discharge.
Keywords
deep vein thrombosis, endovenous intervention, new oral anticoagulants, post-thrombotic syndrome
1Arizona Cardiovascular Consultants & Vein Clinic, Mesa, AZ, USA
2A.T. Still University, Mesa, AZ, USA
Corresponding author:
Mohsen Sharifi
Arizona Cardiovascular Consultants & Vein Clinic
3850 E. Baseline Road, Building 1, Suite 102
Mesa, AZ 85206
USA
Email: seyedmohsensharifi@yahoo.com
553882VMJ0010.1177/1358863X14553882Vascular MedicineSharifi et al.
research-article2014
Original Article
Sharifi et al. 113
Materials and methods
From September 2011 through June 2013, 127 patients
with acute lower extremity DVT involving femoropopliteal
and iliac veins underwent PEVI plus administration of
NOACs by our group. These patients had significant
symptoms warranting admission to the hospital. They
received the treatment that we offer in our usual practice.
This cohort was retrospectively identified and followed in
a prospective fashion for development of outcomes. The
study was approved by the institutional review board of
A.T. Still University. Informed written consent was
obtained from all patients for the procedure and observa-
tional follow up. The patients’ clinical characteristics are
shown in Table 1.
The patients underwent PEVI from 2 to 32 hours after
admission, with the onset of symptoms from 0 to 95 days
of admission. Parenteral anticoagulation continued
before and throughout PEVI and stopped at the end of
the procedure. Two hours thereafter, oral anticoagulation
was started with NOACs, which was continued for a
minimum of 3 months. No warfarin or other VKAs were
used for the initial 3 months. All patients received a min-
imum of 6 months of oral anticoagulation. There were 25
patients who after 3 months were subsequently bridged
to warfarin due to insurance reasons. Initial parenteral
anticoagulation during hospitalization was with enoxa-
parin in 27 patients (21%) and unfractionated heparin
(UFH) in the remainder. Enoxaparin was given at 1 mg/
kg subcutaneously twice daily. The dose of UFH was
reduced after the initial bolus of 70 U/kg to 8–10 U/kg/
hour during PEVI including the CDT period. The acti-
vated prothrombin time (PTT) was maintained at 60–100
seconds. No bolus of UFH was given during CDT. If the
PTT was less than 60 seconds, only the maintenance
dose was increased. Following termination of PEVI, no
further parenteral anticoagulation was used. The dura-
tion of parenteral anticoagulation was thus not more than
24 hours.
The diagnosis of DVT was made by venous duplex
sonography. All procedures were performed via the pop-
liteal vein with the patient in the prone position. Access to
the popliteal vein was obtained using a micropuncture
needle with ultrasound guidance, with subsequent place-
ment of a 6–8 French sheath. Patients having occlusive
DVT involving two or more contiguous venous segments
(femoropopliteal and iliac veins) underwent CDT for 24
hours and were re-evaluated the next day. No thrombec-
tomy catheters were used in these patients and only an
infusion catheter placed. CDT was completed within 24
hours and not extended beyond this period. The dose of
tPA was 1 mg/hour through the infusion catheter. Patients
having DVT in only one venous segment underwent
same-day completion of treatment with a thrombectomy
device. Thrombectomy was performed using a Trellis
device (Bacchus Vascular, Santa Clara, CA, USA),
Cleaner Catheter (Argon Medical Devices Inc., Athens,
TX, USA), or placement of an infusion catheter with
spraying of the thrombus by forceful hand injection and
subsequent manual aspiration with an 8 French guide
catheter. The mean dose of tPA used with thrombectomy
catheters was 18 ± 3 mg. Fixed lesions deemed to be flow-
limiting >50% stenosis on venography or intravascular
ultrasound underwent stenting. Following the termination
of PEVI, the sheath was removed and hemostasis achieved
by manual compression for 5–10 minutes. Thigh-high
compression stockings at 30–40 mmHg were applied and
all patients were encouraged to ambulate in 1 hour.
Inferior vena cava filters were placed in only 11 patients
who were deemed to be at high risk for iatrogenic pulmo-
nary embolism (PE) based on predictors described
previously.8
Two hours after PEVI, NOACs were given to the patients.
Dabigatran was given at 75–150 mg orally twice daily to 35
patients; rivaroxaban at 20 mg orally daily to 76 patients; and
apixaban at 5 mg orally twice daily in the remainder. New
administration of aspirin at 81 mg daily was given to 75
patients for a minimum of 1 month. This included patients
who had received a stent or were deemed to be of low bleed-
ing risk. An additional 26 patients were already on aspirin for
other reasons in whom aspirin was also continued. There
were eight other patients on clopidogrel and prasugrel for
coronary stents. No changes in the patients’ antiplatelet ther-
apy was made, with the exception of reducing the dose of
aspirin to 81 mg for those who were on higher doses. All
patients were given graded compression stockings at 30–40
mmHg and instructed to wear them for 2 years.
During follow-up, patients underwent a thorough clini-
cal assessment and a venous duplex by which the treated
veins were evaluated for reflux and recurrent DVT. Reflux
Table 1. Clinical characteristics of patients.
n=127 (%)
Male 67 (53)
Age 65±10
BMI 32±5
Previous or concomitant dis-
ease, n (%)
Hypertension 55 (43)
Diabetes mellitus 33 (26)
Cardiovascular 44 (35)
Hypercholesterolemia 26 (20)
Pulmonary 17 (13)
Renal 8 (6)
Current smoker 13 (10)
Surgery or trauma (within previ-
ous 3 months)
10 (8)
Estrogen/testosterone therapy 16 (13)
Cancer
Active 19 (15)
History 7 (6)
Known prothrombotic state 8 (6)
Previous VTE 21 (17)
Concomitant PE 27 (21)
Concomitant DVT at other site 25 (20)
On warfarin at presentation 26 (20)
Therapeutic INR at presentation 20 (16)
Data presented as n (%) or mean ± standard deviation.
BMI, body mass index; DVT, deep venous thrombosis; INR, international
normalized ratio; PE, pulmonary embolism; VTE, venous thromboembolism.
114 Vascular Medicine 20(2)
was defined as greater than 1 second of flow reversal on the
spectral Doppler with standing or manual compression.
PTS was evaluated by two methods: our previous defini-
tion (Table 2) and the Villalta score.5,9 Two separate experi-
enced investigators independently evaluated PTS with one
using the Villalta score and the other using our definition.
The assessors were physicians certified by the American
Board of Internal Medicine in cardiovascular diseases or
internal medicine with an interest in vascular medicine who
were well trained in the assessment of PTS. The assessors
were not personally involved in the interventional proce-
dures and subsequent treatment. The utilized interventional
approaches and site of DVT are shown in Table 3.
Follow-up
The patients were seen at 1 week, 1 month, and then at
6-month intervals after discharge.
At each visit, they were evaluated for signs and symp-
toms of recurrent VTE, PTS and bleeding. All patients
underwent a venous duplex scan of the treated venous seg-
ments at 1 month and every 6 months post procedure and at
any time if suspicion of DVT was raised. If PE was sus-
pected, objective testing was performed by pulmonary CT
angiography or radioisotope ventilation perfusion (V/Q)
scanning. Patients who had received a stent had annual
radiography to monitor for stent fracture or kinks. Seven
patients were lost to follow-up. The data are expressed as
mean ± SD.
Results
The mean follow-up was 22±5 months. Using our defini-
tion, PTS developed in five patients (3%), two of whom
were those who had been switched to warfarin. It devel-
oped at 9, 12, 14, 20 and 26 months after PEVI. The
patients’ mean Villalta score was 6.2±0.9. Using the
Villalta score as the initial diagnostic tool, PTS was found
in seven patients (5.5%) with a mean score of 6.1±0.8.
This included all five patients diagnosed using our criteria
plus two additional patients. The degree of PTS was mild
in all irrespective of the methodology used. There was no
in-hospital bleeding. At follow-up, 99 patients were still
on anticoagulation. There were four deaths related to can-
cer and congestive heart failure. One patient developed
bleeding in the iliopsoas muscle at the time of transition to
warfarin and while being on low-molecular-weight hepa-
rin. Another developed minor bleeding from hemorrhoids,
again during the transition period. Four patients on dabi-
gatran were later switched to rivaroxaban due to dyspep-
sia and abdominal pain. Venographic evidence of previous
venous injury was found in 57 patients (45%), many of
whom had no history of such event. This included oblite-
ration of the truncal vein with presence of collaterals,
venous stenosis, multiple tandem lesions, small diameter
vessels, and venous fibrosis and sclerosis as previously
defined.4 There was no PE. Recurrent DVT was found in
two patients who had been switched to warfarin. The
mean duration of hospitalization was 46±9 hours. In 26
patients, 34 self-expandable stents were placed, six of
which were in the femoropopliteal vein and the remainder
in the iliac vein. Venous reflux in the treated venous seg-
ment was found in 29 patients (23%). Compliance with
compression stockings was low. At 6 months only 50
patients were wearing compression stockings. Only 12 of
them were at the recommended 30–40 mmHg pressure;
five were at 15–20 and the remainder at 20–30 mmHg
pressure. At 24 months, 28 patients were still wearing
compression stockings.
Table 2. Definition of PTSa.
Mild PTS Moderate PTS Severe
Edema plus venous refluxb+ ± ±
Skin hyperpigmentation or lipodermatosclerosis – + ±
Healed or active ulcer – – +
aDefinition of PTS is the presence of at least two new symptoms (leg burning, pain, aches, discomfort, restlessness, tingling), plus the above signs.
b More than 1000 ms of reflux on venous spectral Doppler in a segment of the deep venous system without previous reflux or an increase of more
than 500 ms in the extent of reflux if previously present.
+Finding must be present for diagnosis; – finding must be absent for diagnosis; ± presence or absence of finding would not affect diagnosis.
PTS, post-thrombotic syndrome.
Table 3. Interventional approaches used and site of DVT.
Interventional approach n=127 (100%)
CDT overnight 62 (49)
Trellis 25 (20)
Cleaner 11 (9)
Manual power spray 29 (23)
Stenting (in 26 patients) 34 stents (100%)
Lifestar 21 (62)
Protégé 9 (26)
Absolute 4 (12)
IVUS 12 (9)
IVC filter 9 (7)
Site of DVT
Femoropopliteal (excluding iliac DVT) 52 (41)
Iliac (excluding femoropopliteal DVT) 7 (6)
Iliac + femoropopliteal 68 (54%)
Infrapopliteal only 0
Infrapopliteal plus more cephalad 122 (96)
IVC 18 (14)
Left-sided 85 (67)
Bilateral 19 (15)
CDT, catheter-directed thrombolysis; DVT, deep venous thrombosis; IVC,
inferior vena cava; IVUS, intravascular ultrasound.
Sharifi et al. 115
Discussion
The results indicate that in patients undergoing PEVI for
acute DVT, addition of NOACs is highly safe and effective
and associated with a very low PTS rate of 3% or 5.5%
based on the definition used. This rate is lower than the
6.8% observed at 30 months in our previous experience
using the same definition of PTS wherein extended treat-
ment was with warfarin.5 It is substantially less than in the
CaVenT study where the incidence of PTS was 40%.6
NOACs target factor X and II and can dissolve clot-bound
thrombin, a characteristic not seen with VKAs.7 Early
thromboreduction resulting from PEVI reduces the likeli-
hood for valvular damage and associated reflux. Indeed, the
rate of reflux was low at 23%. In a recent meta-analysis of
three select papers, a trend toward reduction of venous
reflux was noted with a relative risk (RR) of 0.39, although
this value did not reach statistical significance (RR, 0.39;
95% CI, 0.16–1.00).4
The duration of hospitalization was short (less than 2
days). This is in part due to the restriction of CDT to less
than 24 hours, limitation of parenteral anticoagulation up to
the end of sheath removal and early transition to NOACs.
Patients can undergo PEVI while fully anticoagulated.5
There is no need to withhold anticoagulation as is usually
required when intervening in the arterial system.
In the current era, bleeding complications from PEVI
should be very low. In this study and with adherence to
the anticoagulation regimen no in-hospital bleeding was
observed. In the TORPEDO trial, the bleeding rate was
2/91 (2.2%) and all were minor.5 In the CaVenT study,
total bleeding was unacceptably high (at 20%).6 In this
trial, the anticoagulation protocol was substantially dif-
ferent than our practice. The mean duration of CDT was
2.3±1.2 days and in some cases up to 6 days. Parenteral
anticoagulation was given for 5 days prior to PEVI; in
other words some patients were receiving over 11 days of
parenteral anticoagulation and CDT combined, a hospi-
talization duration which is not acceptable in the current
health economy. Furthermore, the anticoagulation was
stopped several hours before PEVI, only to be started
with bolus administration of 5000 units of UFH and a
maintenance dose of 15 U/kg/hour. One hour after sheaths
were pulled, full-dose low-molecular-weight heparin was
given to a patient who had just received full-dose antico-
agulation with UFH.6
In a retrospective review of six case series using
thrombectomy devices, the frequency of bleeding requiring
transfusion was 7.5%.10
The significant variation in the bleeding rate therefore
stems from the differences in the duration and dose of anti-
coagulation and thrombolysis regimens.
In this study, all available NOACs were used based on
their availability and operator’s discretion. The United
States Food and Drug Administration (FDA) approved dab-
igatran, rivaroxaban and apixaban for the treatment of non-
valvular atrial fibrillation in October 2010, November 2011
and December 2012, respectively. Rivaroxaban, dabigatran
and apixaban were approved for treatment of VTE in
November 2012, April 2014 and August 2014, respectively.
Patients with renal insufficiency, bleeding tendencies and
recent surgeries received apixaban. If none of the clinical
conditions described above was present rivaroxaban was
given. Earlier in the study dabigatran was the only available
NOAC. It was given at 150 mg orally twice daily to most
patients. If the patient was frail, had up to moderate renal
insufficiency, weighed less than 50 kg or was over 80 years
of age, the lower dose of dabigatran was used. In this study,
the dose of NOAC used for treatment of DVT was less than
the recommended initial dose. This was due to the fact that
all reported studies had uniformly excluded patients who
had received thrombolysis. We postulated that a modified
dose of NOAC would be appropriate for our patients as all
of them had received some form of thrombolysis.
Furthermore, we did not adhere to the conventional 5 days
of parenteral anticoagulation recommended by the
American College of Chest Physicians.2 Specifically, once
PEVI was finished, no further parenteral anticoagulation
was given. The rationale behind this approach was our pre-
vious observation that with substantial reduction in the
thrombotic mass by PEVI, the requirement for parenteral
anticoagulant therapy is reduced.5 The anticoagulation reg-
imen described resulted in no in-hospital bleeding and
proved to be highly effective.
Role of aspirin
One potential reason for the low PTS rates in this study was
the concomitant use of aspirin. The majority of patients
received at least 81 mg of aspirin. The WARFASA and
combination of WARFASA and ASPIRE trials demon-
strated that use of aspirin for extended therapy for DVT
leads to a 32–40% reduction in the development of VTE as
compared to patients on no therapy.11,12 Prior to the publica-
tion of the above trials we had shown a 37% risk reduction
in the development of PTS in the control arm of the
TORPEDO trial.5 In that arm, patients who were on aspirin
had a statistically lower PTS rate than those not receiving
aspirin. We now add 81 mg of aspirin to our treatment regi-
men for patients presenting for VTE unless there is a clear
contraindication to its use.
Definition of PTS
Our definition of PTS was based on simplicity and objec-
tivity. The scoring system developed by Villalta and col-
leagues has been shown to be valid when measured against
quality of life and anatomic and physiologic markers of
PTS with a high inter-observer agreement.9,13
The presence of five leg symptoms (pain, cramps, pares-
thesia, pruritus, and heaviness) and six signs (skin hyperpig-
mentation, induration, edema, new venous ectasia, redness,
and pain during calf compression) is given a score of 0–3
using the contralateral unaffected leg as the basis for all
evaluations.9,13 This means that 11 items have to be assessed,
each with four possible scores; that is, 44 potential choices.
Notwithstanding its previous validation, the Villalta score
still incorporates substantial amounts of subjective data.
Our definition of PTS encompassed the major features of
the above scoring system, yet it was simpler to assess and
116 Vascular Medicine 20(2)
included objective evidence of venous reflux. However, we
‘underdiagnosed’ two cases of mild PTS when compared
against the Villalta score. PTS was of mild grade in all five
(or seven) patients. By definition, all potential moderate and
severe PTS cases using our definition would be inherently
present in their corresponding severity category using the
Villalta score. Thus, our PTS definition provides a simple
and accurate tool to define PTS.
Limitations of the study
This study was an open-label single-arm study from our
center which prospectively followed patients for outcomes
after being treated by our group. The identification of the
cohort was in a retrospective fashion. Consequently it did
not have the rigor of a prospective randomized trial.
Specifically there was no control group and no independent
adjudication committee. It included all patients whose pres-
entation was deemed to be that of an acute DVT. All avail-
able NOACs were included and their use was governed by
their availability and the discretion of the operator.
Nonetheless this report was a reflection of treatment in the
‘real world’ and for all comers. No patient was excluded for
previous VTE, extent of involvement or chronicity of dis-
ease. All patients, however, had significant symptoms to
warrant admission. Although there was variation in the
extent of DVT and use of NOACs, little heterogeneity in
the interventional treatment was present as it was based on
the current practice approach that we offer to our patients.
Owing to the existing limitations, comparisons between the
outcomes of this report versus other studies should be made
with caution.
Conclusion
We conclude that the combination of PEVI plus NOACs
and aspirin is associated with very low rates of PTS when
compared to historic controls. The resulting PTS severity is
only mild and higher severity levels are eliminated. This
approach leads to very low rates of bleeding and recurrent
VTE and promotes early discharge.
Declaration of conflicting interest
The authors declare that there is no conflict of interest.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
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