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

• Severity of post thrombotic syndrome, resolution of presenting DVT symptoms, the prevalence of valvular reflux and residual thrombus, the degree of clot lysis, and cost-effectiveness. [ Time Frame: within 24 months of randomization ] [ Designated as safety issue: No ]
• Major bleeding, symptomatic pulmonary embolism, recurrent venous thromboembolism, and death [ Time Frame: within 10 days and 24 months after randomization ] [ Designated as safety issue: Yes ]

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.

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

• Deep Vein Thrombosis
• Venous Thrombosis
• Postphlebitic Syndrome
• Venous Thromboembolism
• Post Thrombotic Syndrome

• Experimental: A-Intervention
  PCDT with intrathrombus delivery of 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
  Intervention: Drug: Recombinant tissue plasminogen activator (rt-PA)
• No Intervention: B-Control
  Initial anticoagulant therapy with unfractionated heparin, enoxaparin, dalteparin, or tinzaparin, for at least 5 days, overlapped with long-term oral warfarin (target INR 2.0 - 3.0). Elastic compression stockings will be prescribed

• Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S-545S. Erratum in: Chest. 2008 Oct;134(4):892.
• Kahn SR. The post-thrombotic syndrome: the forgotten morbidity of deep venous thrombosis. J Thromb Thrombolysis. 2006 Feb;21(1):41-8. Review.
• Vedantham S, Millward SF, Cardella JF, Hofmann LV, Razavi MK, Grassi CJ, Sacks D, Kinney TB; Society of Interventional Radiology. Society of Interventional Radiology position statement: treatment of acute iliofemoral deep vein thrombosis with use of adjunctive catheter-directed intrathrombus thrombolysis. J Vasc Interv Radiol. 2006 Apr;17(4):613-6. No abstract available.
• Vedantham S, Vesely TM, Sicard GA, Brown D, Rubin B, Sanchez LA, Parti N, Picus D. Pharmacomechanical thrombolysis and early stent placement for iliofemoral deep vein thrombosis. J Vasc Interv Radiol. 2004 Jun;15(6):565-74.
• Vedantham S, Goldhaber SZ, Kahn SR, Julian J, Magnuson E, Jaff MR, Murphy TP, Cohen DJ, Comerota AJ, Gornik HL, Razavi MK, Lewis L, Kearon C. Rationale and design of the ATTRACT Study: a multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of postthrombotic syndrome in patients with proximal deep vein thrombosis. Am Heart J. 2013 Apr;165(4):523-530.e3. doi: 10.1016/j.ahj.2013.01.024. Epub 2013 Mar 5.
• Comerota AJ. The ATTRACT trial: rationale for early intervention for iliofemoral DVT. Perspect Vasc Surg Endovasc Ther. 2009 Dec;21(4):221-4; quiz 224-5. Epub 2010 Jan 3.

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.
• PE 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 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, CPR, 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).

• McMaster University
• Ontario Clinical Oncology Group (OCOG)
• National Heart, Lung, and Blood Institute (NHLBI)
• BSN Medical Inc
• Genentech
• Covidien
• BayerHealthcare
• Mid America Heart Institute
• Society of Interventional Radiology Foundation
• Massachusetts General Hospital