Pharmacomechanical Catheter-Directed Thrombolysis: An Attractive Option for Prevention of Post-Thrombotic Syndrome?

Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT)

NCT00790335

Washington University School of Medicine

National Institutes of Health. Additional support is provided by four companies (Bayer Healthcare, BSN Medical, Covidien, and Genentech), who play no role in study design, execution, or analysis.

58 participating centers throughout the United States.

692

The ATTRACT study is a phase III, multicenter, randomized, open-label, assessor blinded, parallel two-arm, controlled clinical trial. Adults (aged 16 to 75 years) with acute proximal deep vein thrombosis (DVT) are randomized to standard therapy (anticoagulation and elastic compression stockings), with or without adjunctive pharmacomechanical catheter-directed thrombolysis (PCDT) with recombinant tissue plasminogen activator. Patients who are pregnant, have active malignancy, recent major surgery or obstetrical delivery, an intracranial lesion, or preexisting post-thrombotic syndrome (PTS) are excluded. Randomization is stratified by anatomic extent of DVT and clinical center. Subjects return for follow up at 10 days and 30 days, and at six, 12, 18, and 24 months. The primary efficacy outcome is development of PTS (defined as a score of ≥ 5 using the Villalta PTS scale or venous ulceration) within the 24-month follow-up period. Secondary outcomes include bleeding, quality of life, relief of acute DVT symptoms, and cost-effectiveness (Vedantham S et al. Am Heart. J 2013;165:523).

PTS develops in approximately 40 percent of patients after a first episode of proximal DVT. Clinical manifestations include chronic pain, swelling, heaviness, skin changes, and ulceration of the affected limb, resulting in disability and reduced quality of life. Options for preventing PTS are limited. Elastic compression stockings did not reduce PTS compared with placebo stockings in a recent randomized controlled trial (Kahn SR et al. Lancet. 2014;383:880).

PCDT involves both catheter-directed administration of a thrombolytic agent directly into the venous thrombus and mechanical maceration of the thrombus using a catheter-based device. The primary objective of the ATTRACT trial is to determine whether PCDT, added to standard therapy, reduces the incidence of PTS following an episode of acute proximal DVT.

An effective and safe strategy for prevention of PTS is urgently needed. There is equipoise as to whether PCDT may satisfy this unmet need. Clinical practice guidelines of the American Heart Association and Society of Interventional Radiology suggest consideration of PCDT for selected patients with extensive proximal DVT (Jaff MR et al. Circulation. 2011;123:1788; Vedantham S et al. J Vasc Interv Radiol. 2006;17:435), whereas the American College of Chest Physicians guidelines suggest anticoagulation alone over catheter-directed interventions (Kearon C et al. Chest. 2012;141:e419S). The CaVenT trial showed a 26 percent relative risk reduction in PTS at two years among patients with proximal DVT who underwent catheter-directed therapy (Enden T et al. Lancet. 2012;379:31). The study was small (189 subjects) and was conducted at just four centers in Norway, limiting the strength and generalizability of the evidence.

Perhaps the most important limitation of the ATTRACT trial is the open-label design. Knowledge of treatment assignment could bias assessment of the primary outcome, particularly because it relies on a subjective tool (i.e., the Villalta Scale). To minimize such bias, all clinical outcome evaluators and event adjudicators are blinded to treatment allocation, and patients are given explicit instructions not to disclose their treatment assignment at study visits. If these maneuvers are successful in masking assessors, ATTRACT should provide a definitive answer to whether PCDT is an effective means of preventing PTS.