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The ATTRACT (Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter- Directed Thrombolysis) trial is sponsored by the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) and is a phase-3, open-label, assessor-blind, multicenter, randomized controlled trial (RCT) that will determine whether the routine use of adjunctive pharmacomechanical catheter-directed thrombolysis (PCDT) can prevent postthrombotic syndrome (PTS) in patients with symptomatic, acute, proximal deep vein thrombosis (DVT). The ATTRACT trial will randomize 692 patients to receive either PCDT plus standard DVT therapy (anticoagulant therapy and elastic compression stockings) or standard DVT therapy alone.
Patients will have follow-up visits at 10 and 30 days and at 6, 12, 18, and 24 months after randomization to assess the presence and/or severity of PTS (using the Villalta scale, VCSS [venous clinical severity score], and CEAP [clinical, etiologic, anatomic, pathophysiologic measures]),1-5 generic and venous disease–specific quality of life (using SF-36 and VEINES-QOL measures, respectively),6,7 relief of presenting symptoms (assessed using a Likert pain scale and calf circumference measurements), safety (bleeding, recurrent venous thromboembolism, death), cost effectiveness, and ultrasound imaging endpoints (valvular reflux and residual thrombus).
ARE GREAT GENES ENOUGH?
The ATTRACT research team is proud of the trial's
design not because it is a study promoting catheterbased
intervention but because it is a far-reaching, multidisciplinary
collaboration of the DVT research community
that is seeking to address an important public
health problem. The ATTRACT leadership includes DVT
research leaders from interventional radiology, vascular
surgery, cardiology, pulmonary medicine, epidemiology,
hematology, economics, and biostatistics. The study's
Clinical Coordinating Center (CCC) is based at the
Mallinckrodt Institute of Radiology at Washington
University School of Medicine in St. Louis, Missouri.
The Ontario Clinical Oncology Group at McMaster
University in Hamilton, Ontario, Canada, a renowned
clearinghouse for DVT trials, serves as the ATTRACT
trial's Data Coordinating Center and provides important
methodological and biostatistical expertise to the
study. Core laboratories in vascular ultrasound (VasCore
at the Massachusetts General Hospital in Boston) and
health economics (St. Luke's Mid America Heart
Institute in Kansas City, Missouri) coordinate an ultrasound
substudy and a cost comparison, respectively.
Each of the 50 ATTRACT clinical centers fields a diverse investigator team that includes an endovascular physician, a medical physician, an emergency department physician, and the vascular ultrasound laboratory director at a minimum, of whom many are national DVT research leaders. The trial is primarily sponsored by the NHLBI and receives additional support from four industry partners: BSN Medical (Charlotte, NC) (donating compression stockings), Covidien (Mansfield, MA) (donating funds), Genentech, Inc. (San Francisco, CA) (donating recombinant tissue plasminogen activator), and Medrad Interventional/Possis (Indianola, PA) (donating funds). The Society of Interventional Radiology (which played an important role in trial development), the American Venous Forum, and the American College of Phlebology stand together in public support of the trial.
The ATTRACT trial features the use of two PCDT methods that have spurred excitement within the endovascular community: the isolated thrombolysis technique (using the Trellis peripheral infusion system [Bacchus Vascular, Santa Clara, CA]) and the power pulse technique (using the AngioJet rheolytic thrombectomy system [Medrad Interventional/Possis]). Both techniques enable thrombolytic therapy for DVT to be completed in a single, on-table procedure session, potentially reducing the risks and costs of therapy.8-11
Finally, the United States government health agencies stand firmly behind the study. The NHLBI funds approximately $10.2 million to the study. At the June 2009 ATTRACT Investigator Meeting, Assistant United States Surgeon General James M. Galloway publicly highlighted the trial's importance to the public health, as well as the Surgeon General's strong support for its completion.12
To summarize, the ATTRACT trial would seem to have great “genetic” composition, and therefore, one might conclude that its success is assured. But this would be a mistake; in fact, both distant and recent history provide little basis for complacency. The challenges faced by DVT thrombolysis trials are substantial, and patient recruitment to such studies has been very difficult.13 In previous reviews of enrollment to RCTs of systemic thrombolysis for DVT, less than 20% of screened patients were found to meet study eligibility criteria. More recently, two multicenter trials (including the ambitious, well-designed TOLEDO study) and a prospective cohort study were terminated in part due to the inability to recruit patients in a timely fashion.
CURRENT STATUS OF STUDY START-UP
The start-up process for the ATTRACT trial has been
slow, which is as expected for a complex, 50-site NIH
trial. Issues that have delayed the start of study enrollment
have included: (1) the extended time (3–12
months) for sites to process the study contracts, which
may have been prolonged by the large number of 2009
Recovery Act NIH grant applications (given priority in
most institutions); (2) the NHLBI's decision in mid-2009
to put the study on hold for several months to change
the format of its Data Safety Monitoring Board before
subject enrollment; (3) and the Steering Committee's
decision, based on investigator feedback at the investigator
meeting, to amend the protocol in several ways,
which increased its ease of use at the clinical centers.
To date, there are 41 fully activated sites in the ATTRACT trial (many activated during the second quarter of 2010) and an additional 15 to 20 sites in various stages of start-up. Through June 23, 2010, a total of 41 patients have been enrolled at 17 different sites. The good news is that of the patients who met all eligibility criteria, approximately 40% have agreed to participate. On the other hand, study-wide, approximately 30 patients have been screened per patient enrolled. Together, these findings suggest that the study is indeed feasible but only with aggressive efforts to promote enrollment.
CREATING A NEW PROFESSIONALISM IN
ENDOVASCULAR DVT RESEARCH
The ATTRACT trial falls into the general category of
“medical therapy versus surgical therapy” trials. In such
studies, patients are asked to allow a research team (via
randomization) to determine which of two drastically
different treatment approaches they will receive, and in
ATTRACT, allocation to one treatment arm involves
one to three invasive procedures, a hospital stay, and
significant up-front risk. To complicate matters further,
both treatment options are offered outside the study,
so access to a “new” treatment cannot effectively be
used as a selling point. For such studies to succeed,
strong support from a motivated coordinating center is
essential. The ATTRACT CCC is providing all active sites
with resources including brochures (in English and
Spanish), posters, protocol cards, “Dear Colleague” letter
templates, funds to cover the work efforts of screening
large volumes of patients, a 24/7 telephone hotline,
an interactive study Web site with enrollment tips, a
Patient Recruitment Strategy Guide, and other
resources.
But beyond that, success in the ATTRACT trial will require its participating endovascular physicians to reach for a higher level of “research professionalism” than they may be accustomed to, one that matches that possessed by medical thrombosis researchers, who often conduct far simpler studies (eg, comparing two different durations of warfarin therapy). The reality is that even academic interventional radiologists and vascular surgeons tend to be trained first and foremost as clinicians. In such training programs, little time is spent on learning about clinical trials methodology, study implementation, and strategies to boost patient recruitment. This differs greatly from internal medicine programs, in which training to participate successfully in clinical trials is part of the culture. The success of ATTRACT will depend on the degree to which endovascular investigators can change their culture and thinking in the ways explained in the following sections.
Recognize Clinical Trial Recruitment as a
Distinct Activity
The ATTRACT endovascular physicians have been
successful in building their clinical DVT thrombolysis
practices. However, building a practice is very different from recruiting patients to a clinical trial. To build a
clinical practice, one needs to convince patients and
physicians that the long-term risks of PTS should favor
an aggressive treatment approach. However, most
patients referred in this manner were initially treated
with anticoagulant therapy alone but exhibited symptom
progression that ultimately prompted the physician
to refer and the patient to want a more aggressive
therapy. Most such patients have concluded that standard
therapy is insufficient and will not agree to be randomized
to the control arm (no lysis), and many would
be excluded anyway due to symptom duration exceeding
2 weeks or due to other contraindications. In contrast,
successful recruitment to ATTRACT requires identification
of DVT patients when they are initially diagnosed,
before they have formed an opinion on the
effectiveness of anticoagulant therapy alone. This
requires an entirely different approach based on identification
of large numbers of DVT patients in the vascular
ultrasound laboratory, emergency room, and other
primary care settings. This will require more effective
collaboration between endovascular physicians and the
gatekeeper DVT physicians who have direct access to
presenting DVT patients. Although the Steering
Committee has tried to foster these partnerships, it will
ultimately be up to the site investigators to cultivate
them throughout the study period.
Embrace Clinical Equipoise
Only in 2008 did elective DVT thrombolysis become
an acceptable practice in the published guidelines followed
by the medical physicians who determine initial
DVT care.14 During many years performing these procedures,
endovascular physicians have become accustomed
to providing a “hard sell” in terms of arguing
that the long-term risks of severe PTS mitigate in favor
of the use of PCDT. However, in ATTRACT, a patient can
choose either therapy outside the study, so overselling
the intervention actually discourages enrollment in the
study. In fact, many endovascular physicians quote
excessively high numbers for the expected rates of PTS
and venous ulceration that reflect outdated studies performed
in highly selected patient populations. Modern
prospective studies using validated outcome measures
certainly confirm that PTS is very common (25%–50%
of patients with proximal DVT) but that venous ulcers
are infrequent, making it unclear whether the risks and
costs of PCDT should be routinely incurred.15-18
In addition, physicians generally have strong opinions about whether PCDT is appropriate in specific patients. Most endovascular physicians cringe at the idea of randomizing a 21-year-old woman with left iliofemoral DVT from May-Thurner syndrome to the control arm of an RCT. Similarly, most internists would not think of using PCDT for a 70-year-old man with a femoropopliteal DVT who had a gastrointestinal bleed 4 months ago. However, the trial may be inappropriately negative if the first patient who seems likely to benefit the most from PCDT is kept out. It is important that the study's results can be extrapolated to patients similar to the second patient mentioned because they will be treated with PCDT in clinical practice if the study is positive. Therefore, physicians need to refine their rhetoric and adopt the language of clinical equipoise with patients, recognizing that the same patient is often viewed very differently by physicians across the spectrum.
Actively Seek Available Clinical Research Resources
Most academic institutions and many large private
hospitals have a research infrastructure that exists to
enhance recruitment to clinical trials. One example is
an NIH Clinical and Translation Science Award (CTSA)
program, which usually provides a number of invaluable,
free recruitment resources to investigators.
However, few vascular surgeons, and even fewer interventional
radiologists, are plugged in to their institution's
research resources. It is essential for the ATTRACT
investigators to actively seek out and liberally use such
resources. For example, the CCC discovered that 13
ATTRACT sites have CTSA programs. In communicating
this to the site investigators, it became clear that very
few even knew of their CTSA's existence.
CONCLUSION
In the United States, it is so often true that advances
in knowledge and technology far outpace the ability of
our heterogeneous, complicated medical system to
actually deliver this knowledge and technology to
patients in a manner that improves health outcomes.
The failure to implement these represents the fundamental
Achilles' heel of the United States health enterprise
and is particularly applicable to endovascular DVT
research. In 2010, the endovascular DVT physician community
finds itself at a critical juncture, one that
requires a veritable culture change in the way we have
approached the research aspect of our practices. The
importance of the ATTRACT trial to DVT patients is
widely recognized, but success will require endovascular
physicians to collectively raise their game as research
professionals. It is hoped that this creative evolution will
represent another way in which the ATTRACT trial
pushes the DVT research paradigm forward to enable
the next generation of endovascular therapies to be evaluated with the same skill and resources from which
clinical studies of conventional pharmacological interventions
routinely benefit.
The ATTRACT trial is supported by the NHLBI via grants U01-HL088476 and U01-HL088118. The content of this article is solely the responsibility of the author and does not necessarily represent the official views of the NHLBI or the National Institutes of Health.
Suresh Vedantham, MD, is Professor of Radiology and Surgery, Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, Missouri. He has disclosed that he receives grant/research funding from Genentech, Inc., Covidien, Medrad Interventional/Possis, and BSN Medical. Dr. Vedantham may be reached at (314) 362-2900; vedanthams@mir.wustl.edu.
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