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Ultrasound Findings to Adjust the Duration of Anticoagulation (AESOPUS)

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ClinicalTrials.gov Identifier: NCT00380120
Recruitment Status : Completed
First Posted : September 25, 2006
Last Update Posted : March 18, 2008
Sponsor:
Information provided by:
University of Padova

Tracking Information
First Submitted Date  ICMJE September 22, 2006
First Posted Date  ICMJE September 25, 2006
Last Update Posted Date March 18, 2008
Study Start Date  ICMJE January 1999
Actual Primary Completion Date June 2003   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 17, 2008)
The main efficacy outcome is objectively confirmed recurrent thromboembolism from randomization up to completion of 33 months of follow-up. [ Time Frame: 33 months ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 17, 2008)
To establish clinical and/or laboratory parameters associated with the development of recurrent thromboembolism [ Time Frame: 33 months ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ultrasound Findings to Adjust the Duration of Anticoagulation
Official Title  ICMJE The AESOPUS Study: Ultrasound Findings to Adjust the Duration of Anticoagulation in Patients With Deep Vein Thrombosis
Brief Summary Prospective controlled randomized clinical trial. Consecutive patients with acute proximal deep vein thrombosis (DVT) of the lower extremities, with or without contemporary manifestations of pulmonary embolism, are randomized to receive either a fixed duration of anticoagulant therapy (three months in patients with DVT secondary to transitory risk factors, six months in patients with idiopathic DVT) or a flexible duration of anticoagulant therapy, according to the persistence of residual thrombi, as shown by leg veins ultrasonography (up to 1 year in patients with secondary DVT, up to 2 years in those with idiopathic DVT). All patients are followed up to three years to assess the development of (objectively documented) recurrent thromboembolism. The rate of recurrent thromboembolism is compared between the two study groups, as well as the rate of major bleeding complications occurring during anticoagulation.
Detailed Description

Study patients Consecutive patients with symptomatic proximal-vein thrombosis who have completed three months of anticoagulation will be eligible for the study. Patients with thrombosis occurring in association with recent (less than three months) trauma, surgical intervention or puerperium, prolonged (more than seven days) immobilization from any cause or use of hormonal treatment will be regarded as "secondary thrombosis". All other patients will defined as having idiopathic thrombosis.

Study design and interventions The AESOPUS study is a randomized, multicenter, open trial, with independent and blinded assessment of study outcomes. The study is designed to evaluate the long-term clinical benefit and risk of adjusting the duration of oral anticoagulant therapy based on to the persistence or recanalization of venous thrombosis, as shown by repeated ultrasonography.

Randomization is stratified for secondary versus idiopathic thrombosis and for center. After completing the first uneventful three months of anticoagulation, patients will be randomized to fixed durations of warfarin or to flexible durations. In the fixed duration group, patients with idiopathic deep-vein thrombosis will receive 3 additional months of treatment (for a total treatment duration of 6 months), and patients with secondary deep-vein thrombosis will discontinue treatment (for a total treatment duration of 3 months). In the flexible duration group, patients will have ultrasound at the time of randomization and then at 3, 9, 15 and 21 months if the index event is idiopathic or at 3 and 9 months if the index event is secondary. Anticoagulant therapy will be discontinued if the thrombosis has recanalized. If residual venous thrombosis is detected, treatment will be continued until the following ultrasound testing, and for a maximum of 9 months for secondary and 21 months for idiopathic venous thrombosis. In both groups, warfarin will be adjusted to a target international normalized ratio of 2.0 to 3.0.

Ultrasound assessments of the common femoral and popliteal vein (transverse plane) will be done according to a standardized procedure by independent experts unaware of clinical details and of previous ultrasound findings. Vein diameters will be measured during maximal compression, and considered recanalized in case of a diameter < 2.0 millimeters in a single determination, or a diameter < 3.0 millimeters in two consecutive determinations.

Follow-up, recurrent VTE and bleeding Patients will be followed-up for 33 months to document the incidence of symptomatic recurrent thromboembolism. Follow-up visits will be scheduled in all patients at 3, 9, 15, 21, and 33 months after randomization. Recurrent thromboembolism will be diagnosed by compression ultrasound, ventilation/perfusion scanning, or helical tomography as appropriate. If recurrent thrombosis is suspected in a previously unaffected leg, the sole diagnostic criterion will be incompressibility of a proximal vein. Ultrasound criteria for recurrent ipsilateral thrombosis will be incompressibility of a proximal vein segment initially free from thrombi and/or incompressibility of a proximal vein that has completely recanalized. Nonfatal pulmonary embolism will be defined by a (sub)segmental ventilation-perfusion mismatch on lung scanning or an intraluminal filling defect on spiral computed tomography of the chest. Fatal pulmonary embolism will be diagnosed if it is confirmed at autopsy, if it is anteceded in the immediate period before death by objectively confirmed pulmonary embolism or venous thrombosis, or if it is a sudden death that cannot be explained by a disease or condition other than pulmonary embolism.

Bleeding will defined as major it is clinically overt and associated with a hemoglobin drop of at least 20 g/L or transfusion of al least two units of red cells, is retroperitoneal or intracranial. All outcome events will be reviewed by an independent adjudication committee whose members were unaware of the treatment assigned.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Deep Vein Thrombosis
Intervention  ICMJE
  • Drug: sodium warfarin
    dosage: as much as it is required to prolong the international normalized ratio, checked every 2-3 weeks, between 2.0 and 3.0
  • Drug: Sodium warfarin
    As much drug as it is necessary to prolong the international normalized ratio between 2.0 and 3.0
Study Arms  ICMJE
  • Experimental: 1
    Tailoring the duration of anticoagulation according to the ultrasound persistence of residual vein thrombosis
    Interventions:
    • Drug: sodium warfarin
    • Drug: Sodium warfarin
  • Active Comparator: 2
    Administering a fixed duration of anticoagulation (i.e., discontinue it at the time of randomization in patients with secondary DVT, and prolong it for 3 additional months in patients with idiopathic DVT)
    Interventions:
    • Drug: sodium warfarin
    • Drug: Sodium warfarin
Publications * Prandoni P, Prins MH, Lensing AW, Ghirarduzzi A, Ageno W, Imberti D, Scannapieco G, Ambrosio GB, Pesavento R, Cuppini S, Quintavalla R, Agnelli G; AESOPUS Investigators. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009 May 5;150(9):577-85.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 17, 2008)
538
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE June 2006
Actual Primary Completion Date June 2003   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • acute proximal DVT associated or not with clinically symptomatic pulmonary embolism

Exclusion Criteria:

  • history of previous VTE
  • active cancer
  • indications for permanent anticoagulation
  • contraindications to anticoagulation
  • pregnancy
  • geographical inaccessibility for long-term follow-up
  • life expectancy shorter than 1 year
  • refusal of informed consensus
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00380120
Other Study ID Numbers  ICMJE 10/98
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof. Cesare Scandellari, Department of Medical and Surgical Sciences, University of Padua
Study Sponsor  ICMJE University of Padova
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Paolo Prandoni, MD, PhD Department of Medical and Surgical Sciences, University of Padua, Italy
PRS Account University of Padova
Verification Date March 2008

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP