Bologna 8 April 2022 - Patients 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). These are the results of the APIDULCIS study presented at the 6th Conference of the Arianna Anticoagulation Foundation, held in Bologna, Italy on 1-2 April 2022.
This prospective cohort study, coordinated by Professor Gualtiero Palareti, president of Arianna Anticoagulation Foundation and by Daniela Poli M. D. of the Careggi University Hospital in Florence, 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 (deep vein thrombosis or pulmonary embolism). Patients with positive D-dimer were assigned to extended treatment with low-dose apixaban (2.5 mg twice daily). All subjects were followed-up for 18 months.
Around 10 million people worldwide experience venous thromboembolism (VTE) each year. 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 (1), 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 3 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 authorized 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 -30-60 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 2.5 mg 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 (2).
"In patients younger than 75 years old with unprovoked venous thromboembolism, extended treatment (after the initial and maintenance period) with apixaban 2.5 mgx2 was found to be safe and effective" - explained Professor 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 during the conference, are currently in the "peer-review" phase and must be considered preliminary until their publication in an international scientific journal.
Arianna Anticoagulation Foundation (http://ariannafoundation.org/) is an independent non-profit Foundation that promotes clinical research in the coagulation field and disseminates the results of Italian and international research, as well as contributing to the training of health care professionals and providing patients and family members with all the support necessary to face the therapies in an aware way through it’ s web site www.anticoagulazione.it
- Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, Poli D, Testa S, Tosetto A, Pengo V, Prandoni P; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014 Jul 10;124(2):196-203. doi: 10.1182/blood-2014-01-548065. Epub 2014 May 30. PMID: 24879813.
- Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. doi: 10.1056/NEJMoa1207541. Epub 2012 Dec 8. PMID: 23216615.