RESEARCH
The Post-Thrombotic Syndrome and the ATTRACT Trial
by Dennis Slater, MD
[NEW ENGLAND JOURNAL OF MEDICINE, VOLUME 377; 23, PP 2240-2252]
The Acute Venous Thrombosis: Thrombosis Removal with Adjunctive
Catheter-Directed Thrombolysis trial was designed to address the
following question: Does good thrombolysis reduce the incidence
of severity of the post-phlebitic syndrome in patients with proximal
lower extremity deep vein thrombosis?
The post-thrombotic syndrome (PTS) is defined as chronic limb pain
and swelling and can progress to major disabilities such as leg
ulcerations and impaired quality of life. An estimated 12% of new
cases of chronic venous disease (150,000 patients) and venous
leg ulcers (20,000 patients) incur $261 million and $153 million
respectively in direct medical costs annually. As venous ulcers recur
frequently, an estimated 2 million work days are lost yearly, adding
substantial economic burden and indirect medical costs to the US
annually.
The rationale for rapid clearance of thrombus with catheter-directed
thrombolysis is predicated on 2 problems posed by chronic clots in
the lower extremity venous system: residual clot physically blocks
venous blood flow and backflow causing valvular damage, and
reflux in clotted veins and distal unclotted deep and superficial
veins. Obstruction and reflux elevates venous pressure when
standing and walking, leading to edema, tissue hypoxia and injury,
subcutaneous fibrosis and skin ulceration. Rapid elimination of the
deep vein thrombosis would theoretically restore unobstructed flow
and prevent reflux and ambulatory venous hypertension, thereby
preventing the PTS. Support for the “open vein hypothesis” is based
on studies showing a higher incidence of valvular reflux developing
in veins with delayed clot clearance or residual clot at 6 months
and a lower incidence of valvular reflux in veins with rapid clot
clearance.
The ATTRACT trial utilized pharmacomechanical catheter-directed
thrombolysis (PMCDT) via a catheter introduced directly into the
thrombosis and recombinant tissue plasminogen activator (T-PA)
perfusion via side vents along the catheter at a rate of 0.5 – 0.33
mg/cm thrombus (minimum 4 mg) initially and a total 25 mg/24-
hour session. The trial format was a phase III prospective trial of
692 patients with proximal lower extremity deep vein thrombosis
randomized 1:1 to PMCDT followed by standard anticoagulation
(heparin or low molecular weight heparin for 5 days, then warfarin
for a minimum of 3 months in provoked DVT or indefinitely for
unprovoked DVT) (experimental arm) or standard anticoagulation
only (control arm). Three PMCDT devices were available to
30 THE OPEN JOURNAL
Interventional Radiology – Trellis, AngioJet, and Infusion-First.
All William W. Backus Hospital patients were treated with the
AngioJet.
After initial PMCDT, clean-up of residual thrombus with balloon
angioplasty and/or insertion of endovascular stents (May Thurner
syndrome) were required according to standard practice. The
PTS was scored by the Villalta PTS Scale, a questionnaire
assigning points to 5 patient-oriented symptoms (cramps, itching,
paresthesias, heaviness, and pain) and 6 clinician-observed signs
(edema, skin induration, hyperpigmentation, pain with compression,
venous ectasia, and redness). Each symptom or sign was rated as 0
(absent or minimal), 1 (mild), 2 (moderate), or 3 (severe). The points
were summed as a total score for each leg (0-33), and PTS was
diagnosed if the patient had a total score of 5 or more in the index
leg or an ulcer in the index leg at 6-month interval between 6 and
24 months. Severity was categorized as mild (score 5-9), moderate
(10-14), or severe (greater than 15). Two questionnaires, SF-36 (a
general health assessment) and VEINES (a chronic venous disease-
specific assessment), measured quality of life. A second clinical tool,
the Venous Clinical Severity Score, assigned points (0 absent, 1 mild,
2 moderate, 3 severe) for pain, varicosity, edema, skin pigmentation,
inflammation, induration, and ulceration. Both the Villalta PTS Scale
and the Venous Clinical Severity Score were commonly applied and
verified tools for chronic venous disease.
RESULTS
There was no significance difference in the percentage of patients
with the PTS between 6 and 24 months – 47% in the PMCDT arm vs
48% in the control arm. Moderate and severe PTS occurred in 18%
of patients treated with PMCDT vs 24% controls (relative risk 0.73,
P = 0.04) and severity scores were statistically lower in the PMCDT
arm at all time points. There was reduced pain and leg swelling in
the index leg at day #10 and #30, but no difference in quality of life
at 24 months. The incidence of major bleeding within 10 days was
significantly higher among PMCDT patients (1.7% vs 0.3%, P = 0.05).
The incidence of recurrent DVT was non-statistically higher among
PMCDT patients (12% vs 8%, P = 0.09).
Continued on page 31

CONCLUSION
The stated conclusion of the ATTRACT trial was that PMCDT did
not reduce the incidence of PTS, the primary endpoint. However,
the Villalta Score and the Venous Clinical Severity Score were
lower at all time points between 6 and 24 months in the PMCDT
group, indicating less severe PTS, a secondary endpoint. Despite
the reduction in the severity of PTS-related symptoms, there was
COMMENTARY
By Herb Lustberg, MD
The Interventional Radiology staff at the William W. Backus
Hospital were happy to participate in the ATTRACT Trial, being
such an integral step in obtaining answers to important clinical
catheter directed thrombolysis (CDT) management questions, based
on scientifically obtained prospective randomized trial data. We all
wanted the best for our patients, as well as the trial, and worked
hard to have good individual clinical outcomes as well as accurate
data collection for the trial. Our take-away from the experience and
the article support our previous thoughts about post-thrombotic
syndrome (PTS) and CDT.
For those patients with lower extremity DVT and minimal to mild
symptoms, standard anticoagulation seems the most appropriate
course of clinical action. It carries lower risks for major bleeding
complications and has a similar expected quality of life at 24
months, per the trial.
Similarly, those patients with severe symptoms of lower extremity
DVT, including incapacitating edema, pain and possible perfusion
abnormalities, have an equally clear suggested course. CDT with or
without pharmacomechanical methods seem to be most appropriate
Editor’s Note:
The Eastern Connecticut Hematology Oncology Center and
The William W. Backus Hospital contributed 15 patients to the
ATTRACT trial. Dr. Suresh Vedantham, Professor of Radiology
and Surgery at the Washington University Medical Center in
Saint Louis, MO initially rejected our application to participate in
the ATTRACT trial. The trial was restricted to academic centers,
understandably concerned that community hospitals lacked
the technical expertise in interventional radiology and/or the
clinical data management team to monitor the multiple clinical
tools for assessment of primary and secondary outcomes. After
several emails, our application was again denied. Undaunted
and uninvited, I attended an organizational research seminar for
the ATTRACT trial in Boston, MA and challenged Dr. Vedantham
RESEARCH
no improvement in quality of life at 24 months. Therefore, PMCDT
cannot be recommended as an adjuvant to standard anticoagulation
for proximal lower extremity DVT. Nonetheless, is there room for
clinical judgement in the use of PMCDT for patients with proximal
lower extremity DVT? n
in these cases. Pharmacomechanical methods not only may help
severely afflicted patients to reduce long term effects of their DVT
post-thrombotic syndrome, they may help them to recover faster
from their severe acute symptoms and start their post DVT recovery.
The patients in the middle are the most challenging in decision
making. This is where clinical judgement and honest discussion
(with the care team and the patient) needs to be employed. The
lack of quality of life differences in the trial means CDT cannot
be offered to all. But, considering the mean Villalta score and
mean Venous Clinical Severity scores were significantly better in
the pharmacomechanical thrombolysis group than in the control
group, at all visits between 6 and 24 months this more aggressive
method could be offered to some. As more research is performed
on the open vein hypothesis, these cases may be further stratified
into subsets that could be expected to benefit from interventional
radiology methods of CDT. As always, we will watch for additional
scientific data, and will continue to offer patient venous thrombo-
embolism appropriate interventions in keeping with their wishes as
well as any recommendations from their medical team. n
that if the study proved to be positive, this population of
patients was not going to be referred to tertiary care centers
for treatment. Inclusion of community hospitals was essential
for general applicability of PMCDT. He relented and allowed
us and other community hospitals to participate. Thanks to the
Backus ER staff for recognizing potential study candidates, Dr.
Herb Lustberg and Dr. James Burch for their technical precision,
and Dr. Susan Johnson, Pharm. D. for organizational oversight
and data management, the William W. Backus Hospital had
the fourth highest accrual in the US, the highest accrual among
community hospitals, and a spotless review by the central
research coordinators.
- Dennis Slater MD
FALL 2018 31