Study Overview and Rationale
Study Overview

The ATTRACT Study is an NIH-funded, Phase III, multicenter, randomized, open-label, assessor-blinded, parallel two-arm, controlled clinical trial. The National Heart Lung and Blood Institute (NHLBI) funds the study via grants U01HL088476-01A1 (to Dr. Suresh Vedantham at the Clinical Coordinating Center at Washington University in St. Louis, MO) and U01HL088118-01A1 (to Dr. Clive Kearon, Chair, Data Coordinating Center, Ontario Clinical Oncology Group at McMaster University in Hamilton, Ontario). 

Six hundred ninety-two (692) patients with symptomatic proximal DVT that involves the iliac, common femoral, and/or femoral vein (i.e. large blood clots of the leg) will be randomized (randomly chosen like the flip of a coin) to either receive or not receive a clot-busting treatment for their DVT known as Pharmacomechanical Catheter-Directed Thrombolysis (PCDT). All patients, whether or not they receive PCDT, will receive standard treatment for their DVT, consisting of blood-thinning drugs and the use of elastic compression stockings. Patients will be enrolled over 2-3 years in 40-60 U.S. hospitals, and followed for 2 years. Clinical outcomes will be rigorously assessed to answer 5 key questions:

1. Does PCDT prevent the Post-Thrombotic Syndrome (PTS)?
The primary goal of the ATTRACT Study is to determine if the use of PCDT reduces the occurrence of PTS over the 2-year follow-up period. Accordingly, the study’s primary endpoint is the occurrence of PTS over 2 years follow-up, using the Villalta PTS Scale, a validated measure which assesses 5 common PTS symptoms and 6 common PTS signs. The severity of PTS will also be compared using the Villalta PTS Scale, the Revised CEAP Classification System, and the Venous Clinical Severity Score (VCSS).

2. Does PCDT Improve Quality of Life (QOL)?
General and disease-specific QOL will be compared early (30 days after randomization) and late (6, 12, 18, and 24 months after randomization) using validated questionnaire measures (the Short-Form 36 (SF-36) Survey and the VEINES-QOL/Sym measure).

3. Is PCDT Safe Enough?
Rates of major bleeding, intracranial bleeding, symptomatic pulmonary embolism, recurrent venous thromboembolism, and death at 10 days and 2 years will be compared.

4. Is PCDT Cost-Effective?
Economic outcomes will be compared between the two groups. If PCDT prevents PTS but is more costly than standard therapy alone, a cost-effectiveness analysis will be done to determine the incremental cost per quality-adjusted life-year (QALY) gained. The economic study is coordinated by the Mid America Heart Institute in Kansas City, MO.

5. What is the mechanism by which PCDT Prevents PTS?
Analysis of venograms and ultrasound exams will be done to determine if residual clot and/or valvular reflux, respectively, correlate with PTS risk. The Ultrasound Substudy is being coordinated by VasCore at the Massachusetts General Hospital in Boston, MA.

Study Rationale

The ATTRACT Trial seeks to resolve a major controversy among physicians regarding the best way to treat patients with proximal DVT (large blood clots of the leg).

On the one hand, even when standard blood-thinning drugs are used, 25-50% of DVT patients will develop the Post-Thrombotic Syndrome (PTS), a long-term condition that causes daily pain, heaviness, fatigue, and swelling of the leg. In severe cases, PTS can lead to an inability to walk without significant leg pain, inability to hold a steady job, changes in leg skin color, and/or open sores (leg ulcers). Because PTS results from permanent damage to the leg veins that is caused by the blood clots, many doctors have urged immediate removal of the blood clots when they are first discovered. The results of small studies of surgical clot removal (thrombectomy) and the injection of clot-busting drugs into an IV line in the arm (systemic thrombolysis) or directly into the leg blood clot through a small plastic tube (catheter-directed thrombolysis) all suggest that early clot removal may prevent PTS. As new catheter-based devices appear to enable safer clot removal, many doctors are now using clot-busting treatment for DVT more often. The Society of Interventional Radiology has urged use of clot-busting treatment along with blood-thinning drugs for patients with extensive DVT and low expected bleeding risk.

On the other hand, the American College of Chest Physicians (ACCP) DVT treatment guidelines, which are followed by most medical physicians who treat DVT, have long advised against the routine use of clot-busting treatment, citing safety concerns (mainly the risk of bleeding with use of the clot-busting drugs) and the lack of strong evidence in favor of these more aggressive treatments from large, well-designed clinical trials. Although the new (2008) ACCP guidelines and American Heart Association guidelines (2011) recognize the possible benefit of clot-busting treatments for certain patients with extensive DVT and low bleeding risk, many physicians remain wary about using them routinely without better-designed studies.

The strong possibility of a meaningful benefit to patients from state-of-the-art clot-busting treatments which involve the delivery of clot-busting drugs into the clot through a specially designed device (known as “Pharmacomechanical Catheter-Directed Thrombolysis” or “PCDT”), the potential risks and costs of PCDT, and the lack of physician consensus on the treatment of proximal DVT (a very common condition) provide a compelling scientific and ethical rationale for a well-designed clinical trial to determine if PCDT prevents PTS.

Immediate Impact Upon Public Health: If the trial is positive, this finding will fundamentally change clinical DVT practice and improve health by enabling prevention of PTS, a common, morbid, and expensive condition, in thousands of patients. If PCDT does not prevent PTS or if its risk-benefit ratio proves unfavorable, this finding will improve health by eliminating the routine use of a costly and somewhat invasive therapy. Hence, either study outcome will decrease morbidity from DVT and thereby improve public health.

Future Impact Upon Public Health – A Major Paradigm Shift: If ATTRACT is positive, this finding will validate the Open Vein Hypothesis, catalyze a fundamental change in the current paradigm of initial DVT treatment, and provide a critical driving force toward: a) early referral of DVT patients for PCDT, which should further improve its efficacy; b) extension of PCDT to other DVT subgroups (e.g. recurrent DVT or upper extremity DVT); and c) increased investment in novel clot removal technologies that do not cause bleeding, with extension of Endovascular Thrombolysis to patients who cannot receive current fibrinolytic drugs. Hence, the future impact of ATTRACT will extend well beyond the specific patient cohort and endovascular method that will be studied.