Clinical Question

Does continuing warfarin (Coumadin) for 18 months after an unprovoked pulmonary embolism (PE) reduce the risk of recurrent venous thrombotic events?

Bottom Line

Continuing warfarin therapy for 18 months after an unprovoked PE reduces the risk of recurrent symptomatic venous thromboembolism (VTE). However, benefit beyond 18 months is not maintained after the warfarin is discontinued. (Level of Evidence = 1b)

Synopsis

Patients with unprovoked VTE have a higher risk of recurrence than those with a provoked event. This is the first study to evaluate extended anticoagulation beyond six months for patients with unprovoked PE. The authors enrolled adults (N = 371), 18 years or older, who received six months of therapy with a vitamin K antagonist following their first episode of symptomatic unprovoked PE. Patients randomly continued to receive (concealed allocation assignment) warfarin (target international normalized ratio [INR] = 2 to 3) or placebo for 18 months. The investigators maintained double-blinding with the use of sham INR tests and results for the placebo group. Individuals who assessed outcomes remained masked to treatment group assignment. Complete follow-up occurred for 97.8% of patients at 18 months and for 76.3% at 42 months.

Using intention-to-treat analysis, three of 184 patients in the warfarin group and 25 of 187 in the placebo group developed a symptomatic recurrent VTE during the 18-month treatment period (number needed to treat = 8.5; 95% confidence interval, 5.7 to 15.2). During the same period, four of 184 patients in the warfarin group and one of 187 patients in the placebo group experienced a major bleed (number needed to treat to harm = 61). After discontinuation of therapy at 18 months, the risk of symptomatic recurrent VTE in the warfarin group increased so that over the course of the entire study period (42 months) there was not a significant difference in the number of symptomatic recurrent VTEs between treatment groups. Thus, extending anticoagulation with warfarin beyond six months after an unprovoked VTE reduces the risk of recurrence, but only during the time of anticoagulation.

Study design: Randomized controlled trial (double-blinded)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (any location) with outpatient follow-up

Reference: CouturaudFSanchezOPernodGet alPADIS-PE InvestigatorsSix months vs extended oral anticoagulation after a first episode of pulmonary embolism: the PADIS-PE randomized clinical trial. JAMA2015; 314( 1): 31– 40.