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Multicenter Study
. 2022 Dec 13;6(23):6005-6015.
doi: 10.1182/bloodadvances.2022007973.

D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study

Gualtiero Palareti  1 , Daniela Poli  2 , Walter Ageno  3 , Cristina Legnani  1 , Emilia Antonucci  1 , Eugenio Bucherini  4 , Sophie Testa  5 , Oriana Paoletti  5 , Antonio Chistolini  6 , Alessandra Serrao  6 , Ida Martinelli  7 , Paolo Bucciarelli  7 , Anna Falanga  8 , Alberto Tosetto  9 , Luca Sarti  10 , Daniela Mastroiacovo  11 , Benilde Cosmi  12 , Adriana Visonà  13 , Rita Carlotta Santoro  14 , Nello Zanatta  15 , Elvira Grandone  16 , Lorenza Bertù  3 , Vittorio Pengo  17 , Lucia Caiano  3 , Paolo Prandoni  1
Affiliations
Multicenter Study

D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study

Gualtiero Palareti et al. Blood Adv. .

Abstract

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.5 mg twice daily) only to patients with a positive test. A total of 732 outpatients aged 18 to 74 years, anticoagulated for ≥12 months after a first unprovoked VTE, were included. Patients underwent D-dimer testing with commercial assays and preestablished cutoffs. If the baseline D-dimer during anticoagulation was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286 [39.1%]) were left without anticoagulation. At the first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% confidence interval [CI], 4.5-11.2), including symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) recurrence, death for VTE, and major bleeding occurring in patients off anticoagulation vs that in those receiving apixaban (1.1%; 95% CI, 0.4-2.6; adjusted hazard ratio [HR], 8.2; 95% CI, 3.2-25.3). In conclusion, in patients anticoagulated for ≥1 year after a first unprovoked VTE, the decision to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced-dose apixaban against recurrences. This trial was registered at www.clinicaltrials.gov as #NCT03678506.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Flowchart of the Apidulcis study.
Figure 2.
Figure 2.
Prevalence of first-time-ever positive D-dimer result (above the predefined cutoff levels) in the investigated study population at the serial measurement during (0) and days after anticoagulation withdrawal. The percentages are calculated vs the total number of patients tested.
Figure 3.
Figure 3.
The Kaplan-Meier cumulative event rates for the primary outcomes in patients receiving low-dose apixaban (dotted line) for positive D-dimer and in patients with persistently negative D-dimer in whom anticoagulation was definitively stopped (continuous line).
See this image and copyright information in PMC

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