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F. Couturaud et al.
in 14 patients (cumulative risk, 36.8%) in the warfarin group and 17 patients (cumulative risk, 31.5%) in the placebo group (hazard ratio, 0.72; 95% confidence interval: 0.35-1.46). In conclusion, after a first unprovoked proximal deep-vein thrombosis initially treated for 6 months, an additional 18 months of warfarin therapy reduced the composite of recurrent venous thrombosis and major bleeding compared to placebo. However, this benefit was not maintained after stopping anticoagulation. Clinical registration: this trial was registered at www.clinicaltrials.gov as #NCT00740493.
Introduction
Patients with unprovoked venous thromboembolism have a high risk of recurrence after short-term oral antico- agulant therapy for 3 to 6 months.1-7 Current guidelines suggest indefinite anticoagulation in these patients, although this is supported by only a moderate level of evi- dence.8
Extending anticoagulation beyond 6 months of therapy is highly effective in preventing recurrent venous throm- boembolism as long as treatment is maintained, but exposes patients to an increased risk of bleeding propor- tionate to treatment duration.1-7,9-14
Only a few randomized trials have followed patients during a substantial period (up to 1 or 2 years) after stop- ping anticoagulation to determine whether or not the ben- efit of extended anticoagulant therapy is maintained.5-7,15 In a recent randomized trial comparing an additional 18 months of warfarin with placebo after a first episode of unprovoked pulmonary embolism initially treated for 6 months, we confirmed that the benefit of extended thera- py was not maintained during a 2-year follow-up period after discontinuing anticoagulation.7 However, although the rate of recurrent venous thromboembolism after an unprovoked pulmonary embolism has been reported to be close to that observed after an unprovoked deep-vein thrombosis, there is evidence that the case-fatality rate of recurrence is about 4-fold higher after pulmonary embolism than after deep-vein thrombosis.16,17 Consequently, findings concerning unprovoked pul- monary embolism might not apply to patients with unprovoked deep-vein thrombosis.14
We therefore conducted a multicenter, randomized, double-blind trial in patients with a first episode of unpro- voked proximal deep-vein thrombosis given an initial 6- month course of oral anticoagulant therapy, to assess the benefits and risks of an additional 18 months of treatment with warfarin versus placebo during the study treatment period and during the 24 months following treatment dis- continuation. A further aim was to compare the therapeu- tic effect of an additional 18 months of treatment in patients presenting unprovoked deep-vein thrombosis with that observed in the PADIS-PE trial.7
Methods
Ethical review and study organization
The Prolonged Anticoagulation During Eighteen Months versus Placebo After Initial Six-Month Treatment for a First Episode of Idiopathic Deep-Vein Thrombosis (PADIS-DVT) study was con- ducted in accordance with the ethical principles stated in the Declaration of Helsinki, Good Clinical Practice, and relevant French regulations regarding ethics and data protection. The pro- tocol and all amendments were approved by a central independ-
ent Ethics Committee and written informed consent was obtained from all patients before randomization. The study was supervised by an academic steering committee. Study outcomes (recurrence, bleeding and death) were periodically reviewed by an independ- ent data and safety monitoring committee. The role of this com- mittee was to monitor the progress of the trial and to recommend study discontinuation to the steering committee if it considered that patients’ safety was compromised. The University Hospital of Brest, the study sponsor, had no role in the design or conduct of the trial, data analysis, or preparation of the manuscript.
Participants
Patients aged 18 years or older who had experienced a first episode of symptomatic unprovoked proximal deep-vein throm- bosis and had been initially treated without interruption for 6 (range, 5.5 to 7) months with a vitamin K antagonist [target International Normalized Ratio (INR), 2.0 to 3.0] were eligible for inclusion. Unprovoked proximal deep-vein thrombosis was defined as objectively confirmed symptomatic deep-vein throm- bosis located in the popliteal vein or above18 occurring in the absence of any major reversible risk factor for venous thromboem- bolism within 3 months before diagnosis and in the absence of active cancer or cancer resolved within less than 2 years prior to the diagnosis of the venous thromboembolism. Reversible risk factors included surgery with locoregional or general anesthesia lasting over 30 min, trauma with or without lower limb immobi- lization in a plaster cast, and bed-rest for more than 72 h.4,7,8 Estrogen-containing contraception (used by 6 women) was not considered as a major reversible risk factor. No deep-vein throm- bosis was related to prolonged travel or hormone replacement therapy. All the index proximal deep-vein thromboses were objec- tively diagnosed using leg vein ultrasound.18
The main exclusion criteria were: previous confirmed pul- monary embolism or proximal deep-vein thrombosis, concomi- tant symptomatic pulmonary embolism, recurrent venous throm- boembolism or bleeding during the initial 6 months of anticoagu- lation, known major thrombophilia, indication for vitamin K antagonist therapy for reasons other than venous thromboem- bolism, increased bleeding risk, and life expectancy <18 months (see the Online Supplement for the full list).
All participants were ambulatory patients enrolled in eight French hospital centers from July 13th, 2007 to October 16th, 2013 (last patient/last visit: December 31st, 2016).
Randomization, masking and interventions
Except for the study population, the PADIS-DVT trial design was similar to the previously published PADIS-PE trial.7 After the initial 6 months of anticoagulation, patients were included and randomized to receive either warfarin (target INR, 2.0 to 3.0) or placebo (target sham INR, 2.0 to 3.0) for an additional 18 months using a central computerized internet-based system. Based on a computer algorithm, the randomization list was generated by an independent statistician (ClinInfo SA, Lyon, France) in randomly permuted blocks of four or six, with stratification by center. This list was forwarded to a central anticoagulation clinic not involved
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haematologica | 2019; 104(7)