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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
University Hospital, Brest
ClinicalTrials.gov Identifier:
NCT00740883
First received: August 22, 2008
Last updated: July 7, 2014
Last verified: July 2014
  Purpose

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 Intervention Phase
Pulmonary Embolism
Drug: warfarin
Drug: placebo of warfarin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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.

Resource links provided by NLM:


Further study details as provided by University Hospital, Brest:

Primary Outcome Measures:
  • Symptomatic recurrent venous thromboembolism and serious bleeding [ Time Frame: validated standardized objective tests ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • mortality not due to recurrent venous thromboembolism and bleeding [ Time Frame: medical report and death certificates ] [ Designated as safety issue: No ]

Estimated Enrollment: 374
Study Start Date: July 2007
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a first episode of idiopathic pulmonary embolism who have been treated during 6 months (Plus 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 writting 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 proximale 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00740883

Locations
France
Brest University Hospital
Brest, France, 29609
Sponsors and Collaborators
University Hospital, Brest
Investigators
Study Chair: Francis Couturaud, MD, PhD Equipe d'Accueil 3878
  More Information

No publications provided

Responsible Party: University Hospital, Brest
ClinicalTrials.gov Identifier: NCT00740883     History of Changes
Other Study ID Numbers: RB06.076
Study First Received: August 22, 2008
Last Updated: July 7, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by University Hospital, Brest:
venous thromboembolism
warfarin
duration of anticoagulation
recurrent venous thromboembolism
anticoagulant-related bleeding

Additional relevant MeSH terms:
Embolism
Pulmonary Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Anticoagulants
Warfarin
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 29, 2014