Extended anticoagulant treatment prevents recurrent VTE after first unprovoked PE
An additional 18 months of warfarin treatment in patients with first unprovoked PE improves outcomes versus placebo, although the improvement was not sustained after anticoagulant treatment was discontinued.
Patients who have had a first unprovoked pulmonary embolism (PE) appear to benefit from extended anticoagulant treatment, according to a new study.
Researchers in France performed a randomized, double-blind trial of 371 adult patients who had had a first symptomatic unprovoked PE and had been treated continuously for 6 months with a vitamin K antagonist. An unprovoked PE was defined as one that occurred with no major risk factor for thrombosis. Patients were assigned to receive warfarin or placebo for 18 months and were followed between July 2007 and September 2014. The study's primary outcome was recurrent venous thromboembolism (VTE) or major bleeding 18 months after randomization. Secondary outcomes were recurrent VTE or major bleeding at 42 months, plus VTE alone, major bleeding alone, and death unrelated to PE or major bleeding at 18 and 42 months. The study results were published in the July 7 Journal of the American Medical Association.
One hundred eighty-four patients were assigned to the warfarin group and 187 patients were assigned to the placebo group. Of the 371 patients, 363 (97.8%) came to the 18-month visit and 283 (76.3%) came to the 42-month visit. After 18 months, 4 patients were lost to follow-up and 1 withdrew from the study because of an adverse event. The study's median follow-up was 23.4 months after the treatment period and 41 months overall.
During the 18 months of treatment, the primary outcome occurred in 6 of 184 patients in the warfarin group and 25 of 187 patients in the placebo group (3.3% vs. 13.5%; hazard ratio [HR], 0.22; 95% CI, 0.09 to 0.55; P=0.001). Three patients in the warfarin group had recurrent VTE versus 25 patients in the placebo group (HR, 0.15; 95% CI, 0.05 to 0.43), while major bleeding was noted in 4 warfarin patients and 1 placebo patient (HR, 3.96; 95% CI, 0.44 to 35.89). After the treatment period, symptomatic recurrent VTE occurred in 25 patients in the warfarin group and 14 patients in the placebo group (9.3 events per 100 person-years vs. 4.7 events per 100 person-years); major bleeding occurred in 2 patients in the warfarin group and 4 patients in the placebo group. Over the 42-month study period (18 months of treatment plus 24 months of follow-up), the primary outcome occurred in 33 patients in the warfarin group and 42 patients in the placebo group (20.8% vs. 24.0%; HR, 0.75; 95% CI, 0.47 to 1.18). No between-group differences were seen in rates of VTE, major bleeding, or unrelated death.
The authors noted that their primary outcome included 2 outcome measures that may not have been clinically equivalent, that newer anticoagulants were not examined, and that D-dimer levels were not used to guide therapy, among other limitations. However, they concluded that an additional 18 months of warfarin treatment in patients with first unprovoked PE improves outcomes versus placebo, although the improvement was not sustained after anticoagulant treatment was discontinued.
“Our results suggest that patients such as those who participated in our study require long-term secondary prophylaxis measures,” the authors wrote. “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.”