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Extended Duration of Oral Anticoagulant Therapy After a First Episode of Idiopathic Pulmonary Embolism: a Randomized Controlled Trial. "PADIS-PE" Study. (PADIS EP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00740883
Recruitment Status : Completed
First Posted : August 25, 2008
Last Update Posted : January 12, 2017
Information provided by (Responsible Party):
University Hospital, Brest

Brief Summary:

Rational: After 3 or 6 months of oral anticoagulation for an episode of acute venous thromboembolism (VTE), the risk of recurrent VTE is high (10 to 15% per year) in comparison with a low risk of recurrence if VTE was provoked by a major transient risk factor such as recent surgery (3% per year) independently of the initial presentation (deep vein thrombosis or pulmonary embolism). After a first episode of idiopathic VTE, 3 months of anticoagulation is associated with a very high risk of recurrence (27% per year); however, the benefit-risk of extended duration of anticoagulation (1 to 2 years) remains uncertain, mainly in relation with an increased risk of anticoagulant related bleeding. Therefore, the last ACCP conference group recommended 6 months of oral anticoagulant therapy after a first episode of idiopathic VTE. However, this recommendation is likely to be inadequate for at least two main reasons: (1) no studies compared 2 years to 6 months of anticoagulation after idiopathic VTE; and (2), if the frequency of recurrent VTE is similar after deep vein thrombosis and pulmonary embolism, however, the case fatality rate of recurrent VTE is higher after pulmonary embolism (12%) than after deep vein thrombosis (5%).

Objective : the main objective is to demonstrate that, after 6 months of oral anticoagulation for a first episode of idiopathic pulmonary embolism, 18 months of warfarin therapy is associated with a lower cumulative risk of recurrent VTE and major bleeding in comparison with that on 18 months of placebo. The secondary objectives are: (1) to determine the risk of recurrent VTE after 6 months of warfarin therapy and the presence or the absence of residual lung scan perfusion defect and the persistence or not of elevated D-dimer test; and (2), to determine the impact of extended duration of anticoagulation on the risk of VTE after stopping anticoagulant therapy on a follow-up of 2 years.

Method : French multicenter double blind randomized controlled trial. Inclusion and exclusion criteria and pulmonary diagnostic criteria have been defined. After completing 6 months of oral anticoagulation, a lung scan and D-dimer testing are performed; the investigators and the patients will be unaware of the results of these tests. Then, patients are randomized to receive 18 months of warfarin therapy or 18 months of placebo (the dose of placebo will be adapted according to false computer generated INR). The investigators, the radiologists and the patients are blinded of the treatment allocation. The project will be submitted to national ethical committee and written consent will be obtained from all included patients.

Required number of patients: the expected cumulative frequency of recurrent VTE and major bleeding over 18 months is 4.5% while on warfarin therapy and 16% while on placebo. For a α risk of 5% (to falsely conclude to a true difference) and a β risk of 10% (to falsely conclude to an absence of difference), 178 patients per group should be included. As 5% of patients are expected to be loss, a total of 374 patients is required.

Feasibility: about 50 patients per year are hospitalized in our department of medicine in Brest for an acute episode of idiopathic pulmonary embolism. Four additional centers will participate to the study and have a similar recruitment: HEGP (Pr Meyer, Dr Sanchez), CHU Antoine Béclère (Dr Parent, Pr Simmoneau), CHU Saint Etienne (Pr Mismetti, Pr Décousus), CHU Grenoble (Pr Pison, Pr Carpentier). The study will be coordinated by the Clinical Center of Investigation of Brest Hospital; "true" and "false" INR will be generated by the clinic of anticoagulant of "Ile de France" (Dr Cambus).

Clinical implications: the first consequence of the study is to demonstrate that 6 months of warfarin therapy is inadequate and should be continued for at least 18 additional months after a first episode of idiopathic pulmonary embolism. This study has also the potential to confirm or not the contribution of lung scan and D-dimer testing to appreciate the risk of recurrent VTE after stopping anticoagulant therapy. Lastly, the medical economical impact of such therapeutic management will be evaluated.

Condition or disease Intervention/treatment Phase
Pulmonary Embolism Drug: warfarin Drug: placebo of warfarin Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 374 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Eighteen Months of Oral Anticoagulant Therapy Versus Placebo After 6 Six Months of Anticoagulation for a First Episode of Idiopathic Pulmonary Embolism: a Multicentre Double-blind Randomized Controlled Trial. "PADIS-PE" Study.
Study Start Date : July 2007
Actual Primary Completion Date : October 2015
Actual Study Completion Date : October 2016

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: 1
18 months of active warfarin therapy
Drug: warfarin
18 months of warfarin therapy, once daily

Placebo Comparator: 2
18 months of placebo of warfarin
Drug: placebo of warfarin
18 months of placebo of warfarin therapy, once daily

Primary Outcome Measures :
  1. Symptomatic recurrent venous thromboembolism and serious bleeding [ Time Frame: validated standardized objective tests ]

Secondary Outcome Measures :
  1. mortality not due to recurrent venous thromboembolism and bleeding [ Time Frame: medical report and death certificates ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients with a first episode of idiopathic pulmonary embolism who have been treated during 6 months (Plus 30 days or minus 15 days) using Vitamin K antagonist with a INR between 2 and 3.

Exclusion Criteria:

  • Age < 18
  • warfarin hypersensibility
  • unwilling or unable to give written informed consent
  • distal or proximal deep vein thrombosis
  • Pulmonary embolism which was provoked by a reversible major risk factor
  • major thrombophilia (protein C, S or antithrombin deficiency, antiphospholipids antibodies, homozygous factor V Leiden)
  • previous documented episode of proximal deep vein thrombosis or pulmonary embolism
  • other indication for anticoagulant therapy (e.g.:atrial fibrillation, mechanic valve)
  • patient on antithrombotic agent in whom antithrombotic agent should be started again after stopping anticoagulation
  • pregnancy
  • women without contraception
  • planned major surgery in the next 18 months
  • ongoing cancer or cured cancer in less than 2 years
  • serious bleeding risk (e.g.: gastric ulcer)
  • platelet count less than 100 Giga/l
  • Life expectancy less than 18 months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00740883

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Brest University Hospital
Brest, France, 29609
Sponsors and Collaborators
University Hospital, Brest
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Study Chair: Francis Couturaud, MD, PhD Equipe d'Accueil 3878
Publications automatically indexed to this study by Identifier (NCT Number):

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Responsible Party: University Hospital, Brest Identifier: NCT00740883    
Other Study ID Numbers: RB06.076
First Posted: August 25, 2008    Key Record Dates
Last Update Posted: January 12, 2017
Last Verified: January 2017
Keywords provided by University Hospital, Brest:
venous thromboembolism
duration of anticoagulation
recurrent venous thromboembolism
anticoagulant-related bleeding
Additional relevant MeSH terms:
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Pulmonary Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases