A randomised controlled multicenter trial comparing ultrasound-accelerated catheter-directed thrombolysis combined with standard anticoagulant therapy versus standard anticoagulant therapy alone for acute primary iliofemoral deep vein thrombosis (IFDVT).

Iliofemoral deep venous thrombosis (IFDVT) is associated with significant post
thrombotic morbidity. Approximately 95% of patients with IFDVT treated with
anticoagulant medication have valve incompetence after 5 years. Even more
serious is the relatively high incidence, between 50% and 90%, of Post
Thrombotic Syndrome (PTS) among those patients. PTS is characterized by a
painful, heavy leg, with cramps, paresthesia, pruritus, formation of
varicosities, edema and/or hyperpigmentation of the skin with reduced QOL. In
severe cases (3-5%) PTS even leads to non-healing, extremely painful venous
legs ulcers. Early thrombolysis may reduce the incidence of PTS as compared to
treatment with conventional anticoagulant medication alone. Normal valve
function is more likely retained after early clot lysis. It is suggested that
the presence of both obstruction and reflux, rather than either of these alone,
significantly increases the chances for development of PTS.
Although promising, until now most evidence on catheter directed thrombolysis
(CDT) is derived from case series and little evidence is derived from
randomized clinical trials. Moreover in most cases non informative outcome
measures, like valvular competence, are used instead of incidences of PTS.
Systemic thrombolysis reduces the one year incidence of PTS as compared to
treatment with anticoagulant therapy alone (67% versus 89%), but is associated
with bleeding complications due to a relative high dosage of Urokinase (UK) (8%
versus 0%). Bleeding complications are reduced (0-3,8%) and recanalisation
increased using CDT with UK versus systemic thrombolysis with UK (complete
lysis resp. 76-90% versus 28%). Ultrasound accelerated CDT (UACDT) further
reduces complications, treatment time/dose and improves results.
Catheter directed thrombolysis therapy has the potential to be a good candidate
for frontline therapy for IFDVT. However, due to the relative absence of high
quality evidence derived from prospective randomized controlled clinical trials
it seems imperative to conduct a prospective randomized study to compare the
safety and efficacy of catheter directed thrombolysis to conventional
anticoagulant therapy for IFDVT in relation to the development of post
thrombotic morbidity.
Additional therapeutic advantages of surgical interventions such as
improvement of the health related quality of life (HRQOL) have been reported.
We hypothesize that such improvements could also be reached after catheter
directed thrombolysis, we therefore will also include HRQOL questionnaires in
our prospective study.

Primary Objective: Can catheter directed thrombolytic therapy, for the
treatment of primary IFDVT, safely and effectively reduce post thrombotic
morbidity after one year?
Secondary Objective: Does catheter directed thrombolytic intervention have a
positive effect on the quality of life of patients with primary IFDVT?

We propose to conduct a prospective randomized controlled study comparing
catheter directed thrombolysis with conventional anticoagulant therapy to
conventional anticoagulant therapy alone for patients with acute IFDVT.
Consecutive patients admitted to the emergency room or outpatient department of
the participating centres will be recruited after confirmation of IFDVT.
Patients recently diagnosed with IFDVT at non-participating centres (or their
treating physicians) are allowed to contact our investigators and to
participate (when inclusion and exclusion criteria are met). Patients will be
contacted, informed and offered the opportunity to participate in the study.
After randomization patients will be allocated to either conservative treatment
alone or to catheter directed thrombolysis combined with conservative
treatment.
Conservative treatment consists of compression therapy for 24 months and
anticoagulant treatment with an initial treatment with therapeutic doses of
LMWH (fraxiparine/fraxodi®,) in combination with vitamin K-antagonists
(acenocoumarol® and fenprocoumon®, Addenum B2 * Dosing schemes), followed by
treatment with vitamin K-antagonist alone (after completing LMWH treatment of
at least 5-7 days and after an INR above 2 has been reached on two consecutive
measurements) Or NOACs. Anticoagulant treatment will be installed according to
national and international guidelines (ACCP 2008, CBO 2008) tailored based on
the character of the event (6 months of therapy for idiopathic DVT and 3 months
for provoked DVT).
Catheter directed thrombolysis will be performed in a sub-acute stage of IFDVT,
but no later than 21 days after the onset of complaints. Patients will be
admitted to a clinical ward of one of the participating centerst for the
duration of the active lysis, this will be between 24-96 hours (1-4 nights).
The catheter directed thrombolysis will be performed by a experienced
intervention-radiologist with an Ekos Endowave® system (EKOS Corporation,
Bothell, WA; Addendum C1 * Product information Ekos Endowave®, including C2 *
*CE-markering*). Catheter-directed thrombolysis is a routinely used system for
thrombosis in intervention-radiology. The Ekos Endowave® system uses a standard
guide wire to position the Intelligent Drug Delivery Catheter across the length
of the target clot. The guide wire is then pulled out and replaced with the
Microsonic core (with several miniscule high frequency (2MHz) ultrasound
transducers). The system automatically monitors and controls the microsonic
energy delivery. This system does not fragment the thrombus but only gives a
structural change by which a better penetration of the thrombolytic agent is
achieved. This method is especially suitable for use around venous valves.
Ultrasound techniques are able to penetrate the thrombus around the valve
without destroying the valve itself.
The advantages of the Ekos Endowave-system are that only a small amount of
thrombolytic agent is needed and that the infusion time is significantly
reduced compared to other catheter-directed thrombolytic techniques, thereby
reducing the chance for bleeding complications.
Visits to the outpatient clinic will take place at 3 months, 6 and 12 months
after the event, 3 visits in total. At each visit signs and symptoms of PTS
will be recorded (Villalta-Prandoni, Venous Clinical Severity Score, (VCSS)).
Patients will be followed for the entire duration of the study; assessments on
symptoms of PTS (including Villalta-Prandoni score, VCSS and duplex ultrasound
assessment) and HRQOL will be offered once every year. During the final year
of the study (the year following inclusion of the last study patient), the
visits as part of the extension fase will be clustered on set dates .
Within one week of inclusion and before the visit at 12 months patency of the
venous system will be examined for all patients by MRA-gadovist and duplex
and/or APG . Patency scores as well as PTS scores will be compared between
patients from the intervention group and patients from the conventional therapy
group.
Costs associated with transport to and from the participating centres for
additional imaging (all patients at t0,12 months) and/or thrombolysis
(intervention-group only) will be restituted according to standard guidelines
(0,19 ¤ / km).

Catheter directed thrombolysis will be performed with an Ekos Endowave® system
(EKOS Corporation, Bothell, WA). The system uses a standard guide wire to
position the Intelligent Drug Delivery Catheter across the length of the target
clot. The guide wire is introduced through the popliteal vein. Along the guide
wire the catheter is positioned. The location of the dispersion catheter is
controlled and if necessary adjusted by X-ray. The guide wire is then pulled
out and replaced with the Microsonic core (a miniscule high frequency (2MHz)
ultrasound transducer). The system automatically monitors and controls the
microsonic energy delivery. This system does not fragment the thrombus but only
gives a structural change by which a better penetration of the thrombolytic
agent is achieved. This method is especially suitable for use around venous
valves. Ultrasound techniques are able to penetrate the thrombus around the
valve without destroying the valve itself. The advantage of the Ekos
Endowave-system is that only a small amount of thrombolytic agent is needed,
thereby reducing the chance for bleeding complications. The nature and the
duration of the installed anticoagulant therapy following the intervention will
match the therapy installed in the comparator group. It is expected that in
approximately 60% of patients there will remain a significant venous
obstruction after Ekos endowave® thrombolysis. This will be treated by
percutaneous transluminal angioplasty with stenting.

The most serious side effect of thrombolytic therapy is bleeding. With catheter
directed thrombolysis the total thrombolytic dose is significantly less than
the dose administered with the systemic approach. Localized thrombolysis
thereby minimizes complications due to bleeding. One retrospective study
(Parikh et al, 2008) with the Ekos endowave® system reports major bleeding
rates of 3.8% (2/53), involving NO retroperitoneal or intracranial bleedings.
Furthermore the 2 reported bleedings both occured in postoperative patients.

We therefore think that the current study is justified, more so considering the
fact that a safety analysis will be performed at 6 months after study start to
assess the eventual excess morbidity/mortality rate due to
bleeding.