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

Brief Summary

Official Title: “Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis–The ATTRACT Trial”

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.

  • Study Type: Interventional
  • Study Design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
  • Study Primary Completion Date: May 2016

Detailed Clinical Trial 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

Interventions Used in this Clinical Trial

  • Drug: Recombinant tissue plasminogen activator (rt-PA)
    • Pharmacomechanical catheter-directed thrombolysis, consisting of intrathrombus administration of rt-PA using a catheter/device.

Arms, Groups and Cohorts in this Clinical Trial

  • 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
  • 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

Outcome Measures for this Clinical Trial

Primary Measures

  • Cumulative incidence of Post-Thrombotic Syndrome (Villalta Scale)
    • Time Frame: within 24 months after randomization
      Safety Issue?: No

Secondary Measures

  • 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
      Safety Issue?: No
  • Major bleeding, symptomatic pulmonary embolism, recurrent venous thromboembolism, and death
    • Time Frame: within 10 days and 24 months after randomization
      Safety Issue?: Yes

Criteria for Participation in this Clinical Trial

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).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 16 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • Washington University School of Medicine
  • Collaborator
    • McMaster University
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Suresh Vedantham, M.D., Principal Investigator, Clinical Coordinating Center at Washington University School of Medicine
    • Clive Kearon, MB, MRCP, FRCP(C), PhD, Principal Investigator, Data Coordinating Center at McMaster University-Ontario Clinical Oncology Group
    • Samuel Z Goldhaber, M.D., Study Chair, Brigham and Women’s Hospital

References

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.

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