Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis

Phase 3

Completed

Conditions: Deep Vein Thrombosis
Venous Thrombosis
Postphlebitic Syndrome
Venous Thromboembolism
Post Thrombotic Syndrome

Interventions: Drug: Recombinant tissue plasminogen activator (rt-PA)

Registration Number: NCT00790335

Lead Sponsor: Washington University School of Medicine

Brief Summary: The purpose of this study is to determine if the use of adjunctive Pharmacomechanical Catheter Directed Thrombolysis, which includes the intrathrombus administration of rt-PA--Activase (Alteplase),can prevent the post-thrombotic syndrome(PTS)in patients with symptomatic proximal deep vein thrombosis(DVT)as compared with optimal standard DVT therapy alone.

Detailed Description: Activase, the study drug, is a fibrinolytic drug that is indicated for use in acute myocardial infarction, acute ischemic stroke, and acute massive pulmonary embolism in adults. Previous studies have established the ability of rt-PA to lyse venous thrombus in patients with deep vein thrombosis (DVT), and suggest that successful rt-PA mediated thrombolysis can prevent the post-thrombotic syndrome (PTS), a morbid, late complication of DVT that occurs in nearly 50% of patients.

rt-PA is delivered directly into venous thrombus using a catheter/device which is embedded within the thrombus by a physician under imaging guidance. This method of rt-PA delivery, pharmacomechanical catheter-directed intrathrombus thrombolysis (PCDT),is thought to be safer, more effective, and more efficient than previous methods. The question of whether PCDT using rt-PA improves long-term DVT patient outcomes with acceptable risk and cost has not yet been addressed.

The rationale for performing the ATTRACT Trial is based upon:

* the major burden of PTS on DVT patients and the U.S. healthcare system

* the association between rapid clot lysis and prevention of PTS

* the proven ability of rt-PA to dissolve venous thrombus in proximal DVT

* recent advances in CDT methods which may lower bleeding risk

* the major clinical controversy on whether CDT should be routinely used for first-line DVT therapy

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 692

Inclusion Criteria

Symptomatic proximal DVT involving the iliac, common femoral, and/or femoral vein.

Exclusion Criteria

Age less than 16 years or greater than 75 years.
Symptom duration > 14 days for the DVT episode in the index leg (i.e., non-acute DVT).
In the index leg: established PTS, or previous symptomatic DVT within the last 2 years.
In the contralateral (non-index) leg: symptomatic acute DVT a) involving the iliac and/or common femoral vein; or b) for which thrombolysis is planned as part of the initial therapy.
Limb-threatening circulatory compromise.
Pulmonary embolism with hemodynamic compromise (i.e., hypotension).
Inability to tolerate PCDT procedure due to severe dyspnea or acute systemic illness.
Allergy, hypersensitivity, or thrombocytopenia from heparin, rt-PA, or iodinated contrast, except for mild-moderate contrast allergies for which steroid pre-medication can be used.
Hemoglobin < 9.0 mg/dl, INR > 1.6 before warfarin was started, or platelets < 100,000/ml.
Moderate renal impairment in diabetic patients (estimated glomerular filtration rate [GFR] < 60 ml/min) or severe renal impairment in non-diabetic patients (estimated GFR < 30 ml/min).
Active bleeding, recent (< 3 mo) GI bleeding, severe liver dysfunction, bleeding diathesis.
Recent (< 3 mo) internal eye surgery or hemorrhagic retinopathy; recent (< 10 days) major surgery, cataract surgery, trauma, cardiopulmonary resuscitation, obstetrical delivery, or other invasive procedure.
History of stroke or intracranial/intraspinal bleed, tumor, vascular malformation, aneurysm.
Active cancer (metastatic, progressive, or treated within the last 6 months). Exception: patients with non-melanoma primary skin cancers are eligible to participate in the study.
Severe hypertension on repeated readings (systolic > 180 mmHg or diastolic > 105 mmHg).
Pregnant (positive pregnancy test, women of childbearing potential must be tested).
Recently (< 1 mo) had thrombolysis or is participating in another investigational drug study.
Use of a thienopyridine antiplatelet drug (except clopidogrel) in the last 5 days.
Life expectancy < 2 years or chronic non-ambulatory status.
Inability to provide informed consent or to comply with study assessments (e.g. due to cognitive impairment or geographic distance).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
A-Intervention	Recombinant tissue plasminogen activator (rt-PA)	PCDT with intrathrombus delivery of recombinant tissue plasminogen activator (rt-PA, maximum allowable total dose 35 mg) into the DVT over a period of up to 24 hours. Three methods of initial rt-PA delivery will be used: 1) Trellis-8 Peripheral Infusion System - maximum first-session rt-PA dose 25 mg; 2) AngioJet Rheolytic Thrombectomy System - maximum first-session rt-PA dose 25 mg; or 3) Catheter-directed rt-PA infusion for up to 24 hours at 0.01 mg/kg/hr (maximum 1.0 mg/hr) via a multisidehole infusion catheter. Before and after PCDT, patients will receive standard DVT therapy as in the Control Arm

Primary Outcome Measures

Name	Time	Method
Cumulative Incidence of Post-Thrombotic Syndrome (Villalta Scale)	Between 6 and 24 months after randomization	Patients who experienced one of the following occurrences in the index leg between the 6 month and 24 month post-randomization follow-up visits, inclusive: 1) Villalta score of 5 or greater; 2) leg ulcer; or 3) late endovascular procedure performed to treat severe venous disease. The Villalta scale ranges from 0-33 points, with higher scores being worse.

Secondary Outcome Measures

Name	Time	Method
Major Non-post-thrombotic Syndrome Treatment Failure	Through 24 months	A major non-post-thrombotic-syndrome treatment failure refers to when any of three events occurred in the index leg: 1) an unplanned endovascular procedure to treat severe venous symptoms within 6 months post-randomization; 2) venous gangrene within 6 months; or 3) an amputation within 24 months.
Any (Major + Minor) Bleeding	Within 24 months after randomization	Clinically overt bleeding that occurred within 24 months post-randomization
Recurrent Venous Thromboembolism	Within 24 months after randomization	Symptomatic recurrent venous thromboembolism (DVT and/or PE)
Moderate-to-severe Post-thrombotic Syndrome	Between 6 and 24 months after randomization	Proportion of patients with Villalta score of 10 or higher at any time between the 6 month and 24 month follow-up visits, inclusive. The Villalta scale ranges from 0-33 points, with higher scores being worse.
Death	Within 24 months after randomization	All-cause mortality
Change in General Quality of Life - Physical	Baseline to 24 months post-randomization	Short-Form-36 Health Survey, Version 2, Physical Component Summary (PCS) Scale. Range of scores 0-100 with higher scores representing better quality of life.
Any Treatment Failure	Through 24 months	Composite of PTS and major non-PTS treatment failure
Major Bleeding	Within 24 months after randomization	Defined as clinically overt bleeding that was associated with a fall in the hemoglobin level of at least 2.0 g/dl, transfusion of ≥ 2 units of red blood cells, or involvement of a critical site (e.g. intracranial, intraspinal).
Any (Minor + Major) Bleeding	Within 10 days after randomization	Clinically overt bleeding that occurred through 10 days post-randomization
Venous Clinical Severity Score	At 24 months	Mean VCSS score at the specified follow-up visit; range 0-27 (did not use compression item)
Severity of Post-thrombotic Syndrome (Villalta)	At 24 months	Mean Villalta scale score at specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse.
Change in General Quality of Life - Mental	Baseline to 24 months post-randomization	Short-Form-36 Health Survey, Version 2, Mental Component Summary (MCS) Scale. Range of scores 0-100 with higher scores representing better quality of life.
Change in Venous Disease-specific Quality of Life	Baseline to 24 months post-randomization	Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) questionnaire. Range of scores 0-100 with higher scores representing better quality of life, and higher change scores representing greater improvement from baseline.
Change in Leg Pain Severity	Baseline to 30 days post-randomization	Likert pain scale ranging from 1-7, with higher scores representing a greater intensity of pain
Change in Leg Circumference	Baseline to 30 days post-randomization	Mean calf circumference measured 10 cm below the tibial tuberosity

Trial Locations

Locations (56): Arrowhead Hospital/Phoenix Heart, PLLC
🇺🇸
Glendale, Arizona, United States
St. Joseph Hospital
🇺🇸
Orange, California, United States
Stanford University Medical Center
🇺🇸
Stanford, California, United States
Danbury Hospital
🇺🇸
Danbury, Connecticut, United States
Eastern Connecticut Hematology and Oncology Associates
🇺🇸
Norwich, Connecticut, United States
Christiana Care Health Systems
🇺🇸
Newark, Delaware, United States
Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Mease Countryside Hospital
🇺🇸
Clearwater, Florida, United States
Baptist Cardiac & Vascular Institute
🇺🇸
Miami, Florida, United States
Florida Hospital
🇺🇸
Orlando, Florida, United States
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Arrowhead Hospital/Phoenix Heart, PLLC
🇺🇸Glendale, Arizona, United States