Optimal Duration of Anticoagulation for Unprovoked Pulmonary Embolism

By Samuel Nadler, MD, PhD

Critical Care, Pulmonary Medicine, The Polyclinic Madison Center, Seattle

Dr. Nadler reports no relationships relevant to this field of study.

SYNOPSIS: Treatment for 24 months with oral anticoagulation for unprovoked, first-time pulmonary embolism was superior to treatment for 6 months only.

SOURCE: Couturaud F, 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.

Long-term treatment of pulmonary embolism (PE) with oral anticoagulant therapy is the standard of care, but the duration of therapy has not been well established. Based largely on a single, non-blinded study, the American College of Chest Physicians (ACCP) recommended that an unprovoked PE be treated with at least 3 months of oral anticoagulant therapy (Evidence: Grade 1B) with an extended course of treatment if the bleeding risk is low to moderate (Evidence: Grade 2B); similarly, the European Society of Cardiology recently recommended at least 3 months of therapy (Evidence: Class I, Level A) with extended therapy in patients with low bleeding risk (Evidence: Class IIa, Level B).^1,2

The PADIS-PE study is a randomized, double-blind trial of adult patients with a first episode of unprovoked PE that seeks to better define the appropriate duration of therapy. In this study, 371 patients with radiographically confirmed PE who had already completed 6 months of therapy with a vitamin K antagonist were randomized to an additional 18 months of therapy or placebo. Unprovoked PE was defined by the absence of any reversible risk factor within 3 months of the PE, such as surgery, trauma, and bed rest, for more than 72 hours and the absence of active cancer within the last 2 years. Patients were excluded if they had previously experienced a deep vein thrombosis (DVT) or PE, had an independent indication for anticoagulation, had bleeding during the initial 6 months of therapy, had known thrombophilia, increased bleeding risk, platelets < 100,000, were expecting major surgery in the upcoming 18 months, or had a life expectancy of < 18 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding within the 18-month trial period. This outcome was reassessed 24 months after the treatment period was completed.

During the 18-month trial period, treatment with warfarin reduced the primary endpoint significantly (HR, 0.22; CI, 0.01-1.20; P = 0.001.). This effect was due to a reduction in the rate of recurrent venous thromboembolism in the treatment group compared with the placebo group (1.7% vs 13.5%, HR 0.15, P < 0.001), while there was a non-significant increase in bleeding in the warfarin group (2.2% vs 0.5%, HR 3.96, P = 0.22). Overall, there was no difference in mortality during this period between the two groups (1.1% vs 1.1%, HR 1.32, P = 0.78). In the subsequent 24-month period, while not anticoagulated, the effects of prior treatment were largely lost. The overall rate of recurrent thromboembolism was similar in the former treatment and placebo groups (17.9% vs 22.1%, HR 0.69, P = 0.14), as was the bleeding risk (3.5% vs 3%, HR 1.12, P = 0.85). Mortality was similar in the two groups (9.1% vs 3.6%; HR 1.51; P = 0.45).

COMMENTARY

Previous professional guidelines have recommended “extended” courses of anticoagulation, but the optimal duration of therapy was ill-defined. The PADIS-PE study provides strong evidence that 24 months of vitamin K antagonism is superior to 6 months for the treatment of first-time, unprovoked PE. At the end of the 24-month therapeutic trial, patients were further monitored off therapy (median 41 months total). Interestingly during this period, the overall rates of recurrence of PE in the warfarin and placebo groups became statistically similar, as the warfarin group had 25 additional events while the placebo group experienced only 14 additional episodes of venous thromboembolism. This implies that the underlying cause of the PE, while unknown, had not resolved. This is further supported by the observation in this and other studies that the form of recurrence was similar to the index event. Additionally, the rate of recurrence was almost twice as high in the group that stopped therapy compared with the placebo group, implying that a rebound effect may increase the risk of clot after discontinuation of therapy. Therapy well beyond 24 months, even lifelong, might be beneficial.

As described above, recommendations regarding treatment of PE also vary based on the likelihood of bleeding complications. This study included patients with low, moderate, and high risks of bleeding based on ACCP scoring. These factors include advanced age, previous bleeding, cancer, renal failure, liver failure, diabetes, previous stroke, poor anticoagulant control, frequent falls, and alcohol abuse. This study included 45.7% and 40.7% of patients at high risk (more than two risk factors) in the warfarin and placebo groups, respectively. Unfortunately, no subgroup analysis was performed, but a benefit was demonstrated despite inclusion of this proportion of high-risk patients.

The questions remain: What is the optimal length of treatment, and is there a way to prospectively determine who would benefit from extended anticoagulation? The PROLONG study stratified patients with unprovoked DVT after at least 3 months of treatment based on D-dimer levels and compared rates of recurrence in individuals with normal levels to individuals with elevated levels with or without extended treatment.³ Remarkably, the lowest level of recurrence was in patients with elevated D-dimer levels who then received extended treatment. The HR for recurrence in patients with elevated D-dimer levels without vs with treatment was 5.36 (P = 0.007). As in the PADIS-PE trial, extended anticoagulation was clearly beneficial. Elevated D-dimer levels indicated elevated risk for recurrence and benefit of extended anticoagulation, but normal D-dimer levels did not preclude patients from benefiting from extended anticoagulation. Future development of biomarkers may assist in determining benefit of extended anticoagulation, but current studies suggest that lifelong anticoagulation after unprovoked PE is beneficial.

REFERENCES

1. Kearon C, et al. Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(suppl);e419s-494s.
2. Konstantinides SV, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology. Eur Heart J 2014;35:3033-3080.
3. Palareti G, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006:355:1780-1789.