CT scan showing a PE Credit: Medical College of Georgia
SAN FRANCISCO—New research indicates that extending anticoagulant therapy to 2 years can reduce the risk of recurrent venous thromboembolism (VTE) without increasing major bleeding, but this benefit only lasts while patients are receiving the therapy.
In the PADIS-PE study, patients with a first episode of symptomatic, unprovoked pulmonary embolism (PE) received 6 months of treatment with a vitamin K antagonist (VKA), followed by 18 months of warfarin or placebo.
Patients who received warfarin had a 77% reduction in the relative risk of recurrent VTE or major bleeding while they received treatment. But an additional 2 years of follow-up showed that this benefit was lost once patients stopped anticoagulation.
Francis Couturaud, MD, PhD, of the Brest University Hospital Center in Brest, France, presented these data at the 2014 ASH Annual Meeting as LBA-3.*
He and his colleagues randomized patients to receive warfarin (n=184) or placebo (n=187) for 18 months after their intial VKA treatment. Patients were followed for an additional 24 months after treatment ended.
Most baseline characteristics were similar between the treatment arms, although there was a significantly higher percentage of females in the warfarin arm.
“[Overall,] the mean age was below 60, [and] the mean BMI [body mass index] was below 30,” Dr Couturaud noted. “About 4% of patients had previous cancer [that had been] resolved for more than 2 years, 8% had previous distal DVT [deep vein thrombosis] or superficial venous thrombosis, a quarter of women were on estrogen-containing pills, and about one-third had an associated proximal DVT at the time of PE diagnosis.”
“Before the randomization, the mean duration of VKA [therapy] was 6 months, and the mean percentage of time within the therapeutic range was 70. At inclusion, about one-third of patients had residual perfusion defect, about 15% had residual DVT, the mean D-dimer level was below 500 μg/L, and about 27% had thrombophilia.”
Results
The study’s primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Significantly fewer patients met this endpoint in the warfarin arm than in the placebo arm—6 (3.3%) and 25 (13.5%), respectively (hazard ratio [HR]=0.23, P=0.0004).
Likewise, the number of patients with recurrent VTE at 18 months was significantly lower in the warfarin arm than in the placebo arm—3 (1.7%) and 25 (13.5%), respectively (HR=0.11, P<0.0001).
On the other hand, there was no significant difference in the rate of major bleeding between the treatment arms at 18 months. Four patients (2.2%) had major bleeding in the warfarin arm, as did 1 (0.5%) in the placebo arm (HR=4.07, P=0.18).
At 42 months, there was no significant difference between the treatment arms with regard to the composite outcome, the rate of recurrent VTE, or the rate of major bleeding.
The composite outcome occurred in 33 (20.8%) patients in the warfarin arm and 42 (24%) in the placebo arm (HR=0.74, P=0.19). Recurrent VTE occurred in 28 (17.9%) and 39 patients (22.1%), respectively (HR=0.67, P=0.10). And major bleeding occurred in 6 (3.5%) and 5 patients (3%), respectively (HR=1.12, P=0.71).
“[E]xtending anticoagulation for 18 additional months was associated with a major relative risk reduction of 77% of recurrent VTE or major bleeding during the treatment period,” Dr Couturaud said in summary. “However, this benefit was lost during a long-term follow-up of 2 years after stopping anticoagulation.”
“In addition, recurrent VTE occurred in 80% of cases as recurrent PE and in 90% of cases as unprovoked VTE. So additional investigations are needed to identify subgroups of patients at lower risk who may not need indefinite anticoagulation.”
This study was sponsored by Brest University Hospital. Investigators received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, LEO Pharma, and Bayer.
*Information in the abstract differs from that presented at the meeting.