Extended warfarin delays return of unprovoked pulmonary embolism

Adding an extra 18 months of warfarin therapy to the standard 6 months of anticoagulation delays the recurrence of venous thrombosis in patients who have a first episode of unprovoked pulmonary embolism – but the risk of recurrence resumes as soon as the warfarin is discontinued, according to a report published online July 7 in JAMA.

“Our results suggest that patients such as those who participated in our study require long-term secondary prophylaxis measures. Whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or be tailored according to patient risk factors (including elevated D-dimer levels) needs further investigation,” said Dr. Francis Couturaud of the department of internal medicine and chest diseases, University of Brest (France) Hospital, and his associates (JAMA 2015;314:31-40).

Adults with a first episode of unprovoked VT are at much greater risk of recurrence when the standard 6 months of anticoagulation runs out, compared with those whose VT is provoked by a known, transient risk factor such as lengthy surgery, trauma with immobilization of the lower limbs, or bed rest extending longer than 72 hours.

Some experts have advocated extending anticoagulation further in such patients; but whether this is actually beneficial remains uncertain, the investigators said, because most studies have not pursued follow-up beyond the end of treatment.

The researchers performed a multicenter, double-blind trial in which 371 consecutive patients with a first episode of unprovoked PE completed 6 months of anticoagulation and then were randomly assigned to a further 18 months on either warfarin or matching placebo.

During this 18-month treatment period, the primary outcome – a composite of recurrent VT (including PE) and major bleeding – occurred in 3.3% of the warfarin group and 13.5% of the placebo group. That significant difference translated to a 78% reduction in favor of warfarin (hazard ratio, 0.22), Dr. Couturaud and his associates said.

However, after the treatment period ended, the composite outcome occurred in 17.7% of the warfarin group and 10.3% of the placebo group. Thus, the risk of recurrence returned to its normal high level once warfarin was discontinued, the study authors noted.
The study was supported by the Programme Hospitalier de Recherche Clinique (the French Department of Health) and the University Hospital of Brest (France). Dr. Couturaud reported receiving research grants, honoraria, and travel pay from Actelion, AstraZeneca, Bayer, Daiichi Sankyo, Intermune, Leo Pharma, and Pfizer, and his associates reported ties to numerous industry sources.

Related Information

• Computed tomographic pulmonary angiography (CTPA) may be useful in the diagnosis of suspected PE, wrote Dr. Gregoire Le Gal and co-authors from the University of Ottawa. Alternately, a V/Q scan may be performed. The complete accompanying article on diagnostic testing methods for suspected pulmonary embolism can be found here.