VTE: Fewer recurrences with low-dose apixaban compared to discontinuation of the anticoagulant after negative D-dimer


ATTRACT trialPatients who have suffered from a first episode of unprovoked venous thromboembolism (VTE) have an eight times higher risk of recurrence if they stop treatment after repeated negative D-dimer tests, instead of continuing with low-dose anticoagulant (apixaban), according to preliminary results of the APIDULCIS study.

This prospective cohort study was coordinated by Gualtiero Palareti (University of Bologna, Bologna, Italy), president of the Arianna Anticoagulation Foundation and by Daniela Poli (Careggi University Hospital, Florence, Italy). It involved about 800 patients from 49 Italian hospitals with the aim to assess the efficacy and safety of a management procedure, involving repeated D-dimer testing, to select patients who could  safely avoid extended anticoagulation after having completed one year of therapy with oral anticoagulants for a first episode of unprovoked VTE. Patients with positive D-dimer were assigned to extended treatment with low-dose apixaban (2.5mg twice daily). All subjects were followed up for 18 months.

According to the “Arianna Anticoagulazione” Foundation, which funded the non-profit APIDULCIS study, around 10 million people worldwide experience VTE each year, and more than one third of patients who have had a first episode not provoked by transient conditions (such as surgery or trauma) will relapse in the next 10 years. Currently, there are few tools for identifying patients at low risk of recurrence; therefore, the international guidelines recommend extended anticoagulant treatment (without predefined stop date) after a first episode of unprovoked VTE, if the bleeding risk is not high.

Previous studies, among which the DULCIS study, published in Blood in 2014, documented the usefulness of repeated dosing of a blood test, D-dimer, carried out before and after the discontinuation of anticoagulant therapy, to identify patients at low risk of recurrences that could safely discontinue anticoagulation, after the treatment period for the acute episode (at least three months). However, these studies were conducted when the drugs in use for oral anticoagulant therapy were vitamin K antagonists (VKA). In recent years, several direct oral anticoagulants (DOACs) have entered clinical practice for the treatment and prophylaxis of VTE, two of these (apixaban and rivaroxaban) have also been authorised at low doses for the prevention of recurrence in the long term.

Most patients with VTE are currently being treated with DOAC. The aim of the APIDULCIS study was to evaluate whether, in this new context, was it safer for the patient who had completed one year of treatment for a first episode of unprovoked VTE (or associated with a minor risk factor), to continue with low-dose anticoagulant or to stop treatment after negative D-dimer testing (at the time of discontinuation and after 15, 30, and 60 days). The study involved subjects between 18 and 75 years at low risk of bleeding. All patients with positive D-dimer test, considered at high risk, were prescribed apixaban 2.5mg twice daily.

The study was prematurely interrupted in November 2021 due to an excess of recurrences of VTE among the 286 patients (39.1% of the total) who stopped anticoagulation after negative D-dimer tests. Only 1.1% of the 533 patients who received low-dose apixaban had a primary outcome (VTE recurrence or major bleeding) compared with 7.3% of those who discontinued treatment (0.9 vs. 6.2 per 100 person-years). The risk of VTE recurrence was 8 times higher for the patients who stopped therapy. The rate of major bleeding was very low in both groups. The overall incidence of venous and arterial thrombosis in the treatment group was 1.7%, confirming the results of previous studies.

“In patients younger than 75 years old with unprovoked VTE, extended treatment (after the initial and maintenance period) with apixaban 2.5mgx2 was found to be safe and effective,” explained Palareti, coordinator of the study. “In this context, the serial dosage of D-dimer did not allow to identify a group of low-risk patients in which it was safe to discontinue therapy,” he continued, “however, we must remember that the patients considered were all at low risk of bleeding and at high risk of thrombosis.”

The APIDULCIS study is a spontaneous and non-profit study funded by the “Arianna Anticoagulazione” Foundation. BMS-Pfizer provided the drug necessary for the trial free of charge.

The results of the research, presented at the 6th Conference of the Arianna Anticoagulation Foundation (1–2 April, Bologna, Italy) are currently in the “peer-review” phase and must be considered preliminary until their publication in an international scientific journal.


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