Prolonged Anticoagulation After a First Episod of Idiopathic Proximal Deep Vein Thrombosis (PADIS TVP)

Recurrent Venous Thromboembolism Clinical Trial

— PADIS TVP  

Official title:

Eighteen Months of Oral Anticoagulant Therapy Versus Placebo After 6 Six Months of Anticoagulation for a First Episode of Idiopathic Proximal Deep Vein Thrombosis: a Multicentre Double-Blind Randomized Controlled Trial. "PADIS-TVP" Study.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00740493
• Other study ID #: RB06.019 PADIS TVP
• Status: Completed
• Phase: Phase 3
• First received: August 22, 2008
• Last updated: January 11, 2017
• Start date: July 2007
• Est. completion date: January 2017

Study information

• Verified date: January 2017
• Source: University Hospital, Brest
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: French Data Protection AuthorityFrance: Institutional Ethical CommitteeFrance: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

In a French multicenter double blind randomized controlled trial, the main objective is to demonstrate that, after 6 months of oral anticoagulation for a first episode of idiopathic proximal deep vein thrombosis, 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.

Description:

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 proximal deep vein thrombosis, 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 deep vein thrombosis diagnostic criteria have been defined. After completing 6 months of oral anticoagulation, a leg ultrasound 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 has been accepted by 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 deep vein thrombosis. 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 proximal deep vein thrombosis. This study has also the potential to confirm or not the contribution of ultrasound of lower limb 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: January 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with a first episode of idiopathic proximal deep vein thrombosis 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 deep vein thrombosis or pulmonary embolism

• Proximal deep vein thrombosis 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Idiopathic Deep Vein Thrombosis
• Recurrent Venous Thromboembolism
• Thromboembolism
• Thrombosis
• Venous Thromboembolism
• Venous Thrombosis

Intervention

Drug:
• warfarin
18 months of warfarin therapy
• placebo of warfarin
18 months of placebo of warfarin therapy

Locations

Country	Name	City	State
France	CHRU de Brest	Brest
France	CHU de Grenoble	Grenoble
France	Centre Hospitalier Pierre Le Damany	Lannion
France	Centre Hospitalier de Bretagne Sud	Lorient
France	Centre Hospitalier Universitaire de Nantes	Nantes
France	AP HP Hôpital Hôtel Dieu	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	CHU de POITIERS	Poitiers
France	Centre Hospitalier de Cornouaille	Quimper
France	CHU de Rennes	Rennes
France	Centre Hospitalier de Saint Brieuc	Saint Brieuc
France	Hôpital de Rangueil	Toulouse
France	CHU de Tours	Tours
France	Centre Hospitalier Intercommunal	Vernon

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Brest

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	symptomatic recurrent venous thromboembolism and serious bleedings		validated standardized objective tests	No
Secondary	mortality due to another cause than recurrent venous thromboembolism or serious bleeding		medical report and death certificates	No