MedicalResearch.com Interview with:
Professor Francis Couturaud, MD, PhD
Department of Internal Medicine and Chest Diseases
University Hospital Center of Brest
Medical Research: What is the background for this study? What are the main findings?
Dr. Couturaud: Patients who have completed 3 to 6 months of anticoagulation for a first episode of pulmonary embolism that was not provoked by a major transient risk factor, such as surgery or prolonged immobilization, have a high risk of recurrent venous thromboembolism after stopping anticoagulation. In this high-risk population, extending anticoagulation beyond 3 to 6 months is associated with a major reduction in recurrences as long as the treatment is continued. However, whether this benefit is maintained thereafter remains uncertain, as in most previous studies, patients were not followed after treatment discontinuation. In addition, while extending anticoagulation is very effective in preventing recurrent venous thromboembolism, anticoagulation is also associated with an increased risk of bleeding. Therefore, in patients with a first episode of unprovoked pulmonary embolism, the optimal duration of anticoagulation remains uncertain.
In the PADIS-PE multicenter, double-blind, randomized trial that included 371 patients with a first episode of unprovoked pulmonary embolism initially treated during 6 months, we aimed to evaluate the benefit and risk of an additional 18 months of warfarin therapy versus placebo during the 18-month study treatment period and during an additional 2 years of follow-up after study treatment discontinuation.
The main findings are the followings: during the study treatment period, we found a 80% reduction in the relative risk of recurrent venous thromboembolism or major bleeding, mainly driven by the 90% risk reduction of recurrences; however, during the post-treatment follow-up period of two years, the benefit was lost, and the risks of recurrent venous thromboembolism and major bleeding were not different between the 2 groups. In addition, recurrent venous thromboembolism occurred as pulmonary embolism in 80% of cases (8% were fatal) and were unprovoked in 90% of cases.
Medical Research: What should clinicians and patients take away from your report?
Dr. Couturaud: Our study provides convincing result that extended but limited duration of anticoagulation does not improve the long-term prognosis of a first episode of unprovoked pulmonary.
The consequences for clinicians are the followings:
First, only two options of management should be discussed: either a conventional duration of 3 to 6 months or an indefinite duration of anticoagulation.
Second, more than ever, the individual risk factors of recurrent VTE if anticoagulation is stopped and risk factors of bleeding if anticoagulation is continued should be carefully identified and weighted in order to propose the most adequate long-term secondary prevention (long-term anticoagulation or specific prophylactic counseling in high-risk situations). This evaluation should also included patient’s preference.
Third, the benefit risk ratio of indefinite anticoagulation should be serially evaluated in these patients not only if indefinite anticoagulation is decided but also if anticoagulation is stopped as patient’s profile will change over the time (age, additional comorbidities, etc.) and in order to determine if anticoagulation should be stopped or started again.
For the patients, once the first episode of unprovoked pulmonary embolism, they should be informed about their high risk of recurrent venous thromboembolism if anticoagulation is stopped and their risk of bleeding if anticoagulation is continued. They also should be informed that recurrent venous thromboembolism occurs more often as pulmonary embolism; in this setting, patients should be informed about clinical symptoms of pulmonary embolism but also of deep vein thrombosis and the links between these two entities. This will help people to express their preferences.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Couturaud: : The first issue is to identify, among patients with unprovoked venous thromboembolism, those who have a lower risk of recurrence that may not justify indefinite anticoagulation. Several predictive scores, combining clinical variables such at gender, age, and tests such as D-dimer have been derived but prospective validation is not yet available.
The second issue is to explore long-term secondary thrombo-prophylaxis strategies with a lower risk of bleeding and a similar efficacy. This is currently the case with aspirin and low dose of Direct Oral Anticoagulants. However, additional studies are needed to determine if such strategies have a better benefit risk ratio than conventional anticoagulation.
Professor Francis Couturaud, MD, PhD, & Department of Internal Medicine and Chest Diseases (2015). Duration of Anticoagulation After Primary Pulmonary Embolism Clarified