Recurrent Venous Thromboembolism Clinical Trial
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.
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT04042155 -
Real-life Clinical Outcomes of Direct Oral Anticoagulants (MACACOD)
|