Objectives

To determine whether pharmacomechanical thrombolysis prevents post-thrombotic syndrome in patients with proximal deep-vein thrombosis.

Background

Despite the use of anticoagulant therapy, post-thrombotic syndrome develops within 2 years in approximately half of patients with proximal deep-vein thrombosis (DVT). Small randomized trials have suggested that active removal of acute thrombus may preserve venous function and prevent post-thrombotic syndrome.

Pharmacomechanical catheter-directed thrombolysis (hereafter “pharmacomechanical thrombolysis”) is the delivery of a fibrinolytic drug into the thrombus with concomitant thrombus aspiration or maceration. This method is thought to be safer, more effective, and more efficient than previous methods. However, the question of whether this method improves long-term DVT patient outcomes with acceptable risk and cost had not yet been addressed.

Participants

Patients with symptomatic proximal deep-vein thrombosis involving the femoral, common femoral, or iliac vein (with or without other involved ipsilateral veins) were enrolled at 56 clinical centers in the United States. Patients were excluded if they were younger than 16 or older than 75 years of age, were pregnant, had had symptoms for more than 14 days, were at high bleeding risk, had active cancer, had established post-thrombotic syndrome, or had had ipsilateral deep-vein thrombosis in the previous 2 years.

A total of 692 patients underwent randomization. 337 patients were assigned to the pharmacomechanical-thrombolysis group and 355 patients were assigned to the control group.

Design

ATTRACT was a phase 3, multicenter, randomized, open-label, assessor-blinded, controlled clinical trial. Patients were randomly assigned in a 1:1 ratio to the pharmacomechanical-thrombolysis group or the control group. Randomization was stratified according to clinical center and thrombus extent. Patients in each treatment group received initial and long-term anticoagulant therapy consistent with published guidelines and were provided sized-to-fit, knee-high, elastic compression stockings providing 30 to 40 mm Hg of pressure at the 10-day follow-up visit and every 6 months.

For patients in the pharmacomechanical-thrombolysis group, recombinant tissue plasminogen activator (rt-PA) at a dose of <35 mg was delivered into the thrombus by one of three methods. If the popliteal vein was occluded or the inferior vena cava was involved, physicians were required to use “infusion-first” therapy, which started with rt-PA infusion through a multi-sidehole catheter of the physician’s choice for no longer than 30 hours. For the remaining patients, physicians were required to first attempt single-session thrombus removal with rapid delivery of rt-PA through the AngioJet Rheolytic Thrombectomy System or the Trellis Peripheral Infusion System and then to infuse rt-PA for no longer than 24 hours if residual thrombus was present. After the initial delivery of rt-PA, physicians could use balloon maceration, catheter aspiration, thrombectomy with the use of the AngioJet or Trellis system, percutaneous transluminal balloon venoplasty, stent placement (iliac or common femoral vein), or a combination of procedures to clear residual thrombus and treat obstructive lesions. Treatment was discontinued when there was at least 90% thrombus removal with restoration of flow or when there was a serious complication. Thrombus removal was quantified by independent central readers who scored venograms obtained before and after the procedure, using the proximal-vein components of the Marder score. The modified Marder score ranges from 0 to 24, with 0 representing no thrombus and 24 representing complete thrombosis. During the procedure, patients received twice-daily subcutaneous injections of low-molecular-weight heparin in therapeutic doses or unfractionated heparin infusions (with the dose reduced to 6 to 12 units per kilogram of body weight per hour [maximum, 1000 units per hour] during rt-PA infusions). Additional unfractionated heparin boluses (up to 50 units per kilogram) were given during the procedure at the physician’s discretion.

The severity of the post-thrombotic syndrome was evaluated at 6, 12, 18 and 24 months with the use of the Villalta scale and the Venous Clinical Severity Score (in both measures, higher scores indicating more severe post-thrombotic syndrome). Patient-reported health-related quality of life at baseline and 24 months was assessed with the use of the generic Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and the venous disease–specific Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) measure. Leg pain and leg swelling at baseline, 10 days, and 30 days were assessed with the use of a 7-point Likert pain scale (with higher scores indicating more severe pain) and by measuring calf circumference, respectively. Safety outcomes included bleeding, recurrent venous thromboembolism, and death, which were reported throughout follow-up and summarized through 10 days and 24 months. The clinical personnel who performed assessments of efficacy outcomes and the adjudicators of safety and efficacy outcomes were unaware of the treatment assignments.

The primary outcome was development of post-thrombotic syndrome as defined by a Villalta score of 5 or higher or an ulcer in the leg with the index deep-vein thrombosis, at any time between the 6-month follow-up visit and the 24-month follow-up visit.

Conclusions

In conclusion, among patients with acute proximal deep-vein thrombosis, the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of post-thrombotic syndrome but did result in a higher risk of major bleeding.

Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis. N Engl J Med. 2017;377(23):2240-2252. doi:10.1056/NEJMoa1615066

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