French PADIS-PE Trial Evaluates Extended Warfarin Treatment After First PE

July 14, 2015—Francis Couturaud, MD, et al published findings from the PADIS-PE study in the Journal of the American Medical Association (JAMA; 2015;314:31–40). PADIS-PE is a French, multicenter, double-blind, randomized clinical trial evaluating the benefits and risks associated with an additional 18 months of oral anticoagulant therapy (warfarin) versus placebo after 6 months of anticoagulation on a vitamin K antagonist for a first episode of idiopathic pulmonary embolism (PE). The study is chaired by Dr. Couturaud of Brest University Hospital in Brest, France, which is the sponsor of the trial.

The investigators concluded that among patients with a first episode of unprovoked PE who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo; however, the benefit was not maintained after discontinuation of anticoagulation therapy.

As summarized in JAMA, the background of the study is that the optimal duration of anticoagulation after a first episode of unprovoked PE is uncertain. The PADIS-PE investigators enrolled 371 adult patients who had experienced a first episode of symptomatic unprovoked PE (ie, with no major risk factor for thrombosis) and had been initially treated for 6 uninterrupted months with a vitamin K antagonist. The patients were randomized to received warfarin or placebo for 18 months and were followed up between July 2007 and September 2014 at 14 French centers with median follow-up time of 24 months. After randomization, four patients were lost to follow-up, all after 18 months, and one withdrew due to an adverse event.

The primary outcome was the composite of recurrent venous thromboembolism (VTE) or major bleeding at 18 months after randomization. Secondary outcomes were the composite at 42 months (treatment period plus 24-month follow-up), as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding at 18 and 42 months.

The investigators found that during the 18-month treatment period, the primary outcome occurred in six of 184 patients (3.3%) in the warfarin group and in 25 of 187 (13.5%) in the placebo group. Recurrent VTE occurred in three patients in the warfarin group and 25 patients in the placebo group; major bleeding occurred in four patients in the warfarin group and in one patient in the placebo group.

During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (20.8%) in the warfarin group and in 42 (24%) in the placebo group. Rates of recurrent VTE, major bleeding, and unrelated death did not differ between groups, reported the PADIS-PE investigators in JAMA.