After Pulmonary Embolism, Benefit of Secondary Anticoagulation Does Not Persist
Lengthening anticoagulation
therapy beyond 6 months after a first episode of pulmonary embolism reduces the
risk of recurrent venous thromboembolism (VTE) and major bleeding. But the
benefit is lost once the anticoagulant is discontinued, according to results from
the PADIS-PE trial published in the July 7, 2015, issue of the Journal of
the American Medical Association.
For PADIS-PE, Francis Couturaud, MD, PhD, of Hôpital de la Cavale Blanche (Brest Cedex, France), and colleagues randomized 371 patients to treatment with warfarin (n = 184) or matched placebo (n = 187) for 18 months at 14 French centers between July 2007 and March 2012. All patients previously had symptomatic unprovoked pulmonary embolism and were treated for 6 uninterrupted months with a vitamin K antagonist (warfarin 73.4%, fluindione 26.6%) prior to randomization into the trial.
Both groups of patients had similar baseline characteristics, with the exception that a greater percentage of women than men were assigned to warfarin. In the warfarin group, the international normalized ratio (INR) was within the therapeutic range (2.0-3.0) for 69.8% of the time and measured at a mean interval of 19.6 days.
Benefit Lost After Discontinuation
At 18 months, the composite of recurrent VTE or major bleeding (primary outcome) was lower in the warfarin-treated group than in the placebo group, resulting in a relative risk reduction of 78%. The difference was driven by fewer cases of symptomatic recurrent VTE paired with a minimal increase in nonfatal bleeding events. When the entire study period—including treatment and follow-up—is taken as a whole, however, the differences in outcomes were negligible between the warfarin and placebo groups (table 1).
“[T]he risk of recurrence
in the placebo group was greatest during the first 6 months after discontinuing
anticoagulation and increased linearly by 4% to 5% per year,” the investigators
report. Conversely, they say, “the risk of major bleeding during treatment with
warfarin was low, increasing linearly by less than 2% per year.”
How Much, for How Long?
Dr. Couturaud and colleagues acknowledge that it is unclear whether these results will apply to the newer anticoagulants or aspirin. Even so, they say, the findings justify long-term secondary prophylaxis measures in this patient group.
“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,” they add.
A limitation of the study is that it took 7 years to complete, partly due to reluctance of patients to participate in 42 months of follow-up, the investigators note.
Source:
Couturaud
F, Sanchez O, Pernod G, et al. Six months vs extended oral anticoagulation
after a first episode of pulmonary embolism: the PADIS-PE randomized clinical
trial. JAMA. 2015;314:31-40.
Disclosures:
- The study was supported by grants from the French Department of Health.
- Dr. Couturaud reports receiving research grant support from Pfizer; honoraria for board memberships or symposia from AstraZeneca and Bayer; and travel support from Actelion, Bayer, Daiichi Sankyo, Intermune, and Leo Pharma.
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L.A. McKeown is a Senior Medical Journalist for TCTMD, the Section Editor of CV Team Forum, and Senior Medical…
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