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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Deep Vein Thrombosis; Venous Thrombosis; Postphlebitic Syndrome; Venous Thromboembolism; Post Thrombotic Syndrome	Drug: Recombinant tissue plasminogen activator (rt-PA)	Phase 3

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

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	692 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis--The ATTRACT Trial
Study Start Date :	November 2009
Actual Primary Completion Date :	January 2017
Actual Study Completion Date :	January 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: A-Intervention; 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	Drug: Recombinant tissue plasminogen activator (rt-PA); Pharmacomechanical catheter-directed thrombolysis, consisting of intrathrombus administration of rt-PA using a catheter/device.; Other Names: rt-PA; recombinant tissue plasminogen activator; Activase; Alteplase
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 international normalized ratio 2.0 - 3.0). Elastic compression stockings will be prescribed

Outcome Measures

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Primary Outcome Measures :

1. Cumulative Incidence of Post-Thrombotic Syndrome (Villalta Scale) [ Time Frame: 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 :

1. Major Non-post-thrombotic Syndrome Treatment Failure [ Time Frame: 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.
2. Any Treatment Failure [ Time Frame: Through 24 months ]
   Composite of PTS and major non-PTS treatment failure
3. Moderate-to-severe Post-thrombotic Syndrome [ Time Frame: 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.
4. Major Bleeding [ Time Frame: Within 10 days after randomization ]
   Defined as clinically overt bleeding that is 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).
5. Major Bleeding [ Time Frame: 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).
6. Any (Minor + Major) Bleeding [ Time Frame: Within 10 days after randomization ]
   Clinically overt bleeding that occurred through 10 days post-randomization
7. Any (Major + Minor) Bleeding [ Time Frame: Within 24 months after randomization ]
   Clinically overt bleeding that occurred within 24 months post-randomization
8. Recurrent Venous Thromboembolism [ Time Frame: Within 10 days after randomization ]
   Proportion of patients with symptomatic recurrent venous thromboembolism (including DVT and/or PE)
9. Recurrent Venous Thromboembolism [ Time Frame: Within 24 months after randomization ]
   Symptomatic recurrent venous thromboembolism (DVT and/or PE)
10. Death [ Time Frame: Within 10 days after randomization ]
    All-cause mortality
11. Death [ Time Frame: Within 24 months after randomization ]
    All-cause mortality
12. Severity of Post-thrombotic Syndrome (Villalta) [ Time Frame: At 6 months ]
    Mean Villalta scale score at the specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse.
13. Severity of Post-thrombotic Syndrome (Villalta) [ Time Frame: At 12 months ]
    Mean Villalta scale score at the specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse.
14. Severity of Post-thrombotic Syndrome (Villalta) [ Time Frame: At 18 months ]
    Mean Villalta scale score at specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse.
15. Severity of Post-thrombotic Syndrome (Villalta) [ Time Frame: At 24 months ]
    Mean Villalta scale score at specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse.
16. Venous Clinical Severity Score [ Time Frame: At 6 months ]
    Mean Venous Clinical Severity Score (VCSS) at the specified follow-up visit; range 0-27 (did not use compression item), higher score is worse
17. Venous Clinical Severity Score [ Time Frame: At 12 months ]
    Mean VCSS score at the specified follow-up visit; range 0-27 (did not use compression item)
18. Venous Clinical Severity Score [ Time Frame: At 18 months ]
    Mean VCSS score at the specified follow-up visit; range 0-27 (did not use compression item)
19. Venous Clinical Severity Score [ Time Frame: At 24 months ]
    Mean VCSS score at the specified follow-up visit; range 0-27 (did not use compression item)
20. Change in General Quality of Life - Physical [ Time Frame: 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.
21. Change in General Quality of Life - Mental [ Time Frame: 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.
22. Change in Venous Disease-specific Quality of Life [ Time Frame: 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.
23. Change in Leg Pain Severity [ Time Frame: Baseline to 10 days post-randomization ]
    Likert pain scale ranging from 1-7, with higher scores representing a greater intensity of pain
24. Change in Leg Pain Severity [ Time Frame: Baseline to 30 days post-randomization ]
    Likert pain scale ranging from 1-7, with higher scores representing a greater intensity of pain
25. Change in Leg Circumference [ Time Frame: Baseline to 10 days post-randomization ]
    Mean calf circumference measured 10 cm below the tibial tuberosity
26. Change in Leg Circumference [ Time Frame: Baseline to 30 days post-randomization ]
    Mean calf circumference measured 10 cm below the tibial tuberosity

Eligibility Criteria

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Ages Eligible for Study:	16 Years to 75 Years (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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).

Contacts and Locations

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  Show 56 Study Locations

Sponsors and Collaborators

Washington University School of Medicine

McMaster University

Ontario Clinical Oncology Group (OCOG)

National Heart, Lung, and Blood Institute (NHLBI)

BSN Medical Inc

Genentech, Inc.

Medtronic - MITG

Boston Scientific Corporation

Mid America Heart Institute

Society of Interventional Radiology Foundation

Massachusetts General Hospital

Investigators

Principal Investigator:	Suresh Vedantham, M.D.	Clinical Coordinating Center at Washington University School of Medicine
Principal Investigator:	Clive Kearon, MB, MRCP, FRCP(C), PhD	Data Coordinating Center at McMaster University-Ontario Clinical Oncology Group
Study Chair:	Samuel Z Goldhaber, M.D.	Brigham and Women's Hospital

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

The Long-Term Clinical Course of Acute Deep Vein Thrombosis 

Predictors of the Post Thrombotic Syndrome During Long-Term Treatment of Proximal Deep Vein Thrombosis 

Deep Vein Thrombosis 

Below-Knee Elastic Compression Stockings to Prevent the Post Thrombotic Syndrome 

Publications:

Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. 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. doi: 10.1378/chest.08-0658. 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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vedantham S, Goldhaber SZ, Julian JA, Kahn SR, Jaff MR, Cohen DJ, Magnuson E, Razavi MK, Comerota AJ, Gornik HL, Murphy TP, Lewis L, Duncan JR, Nieters P, Derfler MC, Filion M, Gu CS, Kee S, Schneider J, Saad N, Blinder M, Moll S, Sacks D, Lin J, Rundback J, Garcia M, Razdan R, VanderWoude E, Marques V, Kearon C; ATTRACT Trial Investigators. Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis. N Engl J Med. 2017 Dec 7;377(23):2240-2252. doi: 10.1056/NEJMoa1615066.

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. doi: 10.1177/1531003509359311. Epub 2010 Jan 3.

Responsible Party:	Washington University School of Medicine
ClinicalTrials.gov Identifier:	NCT00790335 History of Changes
Other Study ID Numbers:	22326953211; U01HL088476-01A1 ( U.S. NIH Grant/Contract )
First Posted:	November 13, 2008
Results First Posted:	March 29, 2018
Last Update Posted:	March 29, 2018
Last Verified:	February 2018

Keywords provided by Washington University School of Medicine:

deep vein thrombosis; deep venous thrombosis; post thrombotic syndrome; blood clot; thrombolysis; tissue plasminogen activator	rt-PA; Activase; mechanical thrombectomy; pharmacomechanical; ATTRACT

Additional relevant MeSH terms:

Syndrome; Thrombosis; Thromboembolism; Venous Thromboembolism; Venous Thrombosis; Postthrombotic Syndrome; Postphlebitic Syndrome; Disease; Pathologic Processes; Embolism and Thrombosis	Vascular Diseases; Cardiovascular Diseases; Venous Insufficiency; Phlebitis; Peripheral Vascular Diseases; Plasminogen; Tissue Plasminogen Activator; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action