Clinical trial NCT03678506: Apixaban for Extended Anticoagulation (APIDULCIS)
Official title: APIDULCIS: Extended Anticoagulation With Low-dose Apixaban After a Standard Course Anticoagulation in Patients With a First Venous Thromboembolism Who Have Positive D-dimer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Venous Thromboembolism
Anticoagulants
Keywords: Venous thromboembolism
D-Dimer
Apixaban
Extended treatment
Lead sponsor: Arianna Anticoagulazione Foundation
Sponsor class: OTHER
First posted: 2018-09-19
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The patients included in the study will receive a serial determination of D-dimer assay (a maximum of four determinations in case of negative results).The D-dimer measurements should be performed at the moment of patient screening, when patients still assume their anticoagulant treatment (T0), at 15±2 days (T1), 30±4 days (T2), and 60±5 (T3) days after their anticoagulant treatment has been stopped. At the first positive D-dimer result patients resume anticoagulation with apixaban 2.5 mg bis in die for the next 18 months. Patients with negative D-Dimer results at all determinations stop anticoagulation definitely and will followed up for the next 18 months.
Primary purpose: PREVENTION

Brief summary: The study aims at optimizing the long-term and extended management of patients with a first episode of venous thromboembolism (proximal deep vein thrombosis with or without pulmonary embolism) (VTE). Patients at high risk of recurrence (with altered D-dimer test), who had received anticoagulation (whatever the drug used) for 12-15 months after the first episode of thrombosis, will be treated with Apixaban 2,5 mg x 2 for 18 months as extended treatment. Patients at low risk, with normal D-dimer test, will stop anticoagulation definitely.

Detailed description: This prospective cohort study aims to assess the efficacy and safety of a management procedure to decide on giving or not an extended anticoagulation (administering apixaban 2 2.5 mg twice daily ) to outpatients with a single episode of proximal deep vein thrombosis of the lower limbs and/or pulmonary embolism who had received 12-15 months of anticoagulation (whatever the anticoagulant drug used). The study seeks to assess whether a management procedure involving D-dimer testing assessment can identify a subset of subjects at low risk of recurrence in whom an extended anticoagulation can be safely avoided.

Eligibility criteria: Inclusion Criteria:

* First unprovoked Venous Thromboembolic Event
* Venous Thromboembolic events associated with one or more risk factors that are no longer present
* Age older than 18 or younger than 75 years
* Capacity to give written informed consent

Exclusion Criteria:

* A) Exclusion criteria regarding the index event
* Events usually associated with low risk of recurrence
* Deep vein thrombosis/ Pulmonary embolism occurred within 3 months from major surgery or major trauma
* Isolated Distal deep vein thrombosis (thrombosis of calf veins)
* Events associated with a very high risk of recurrence or occurrence of life-threatening recurrent events

  * Pulmonary Embolism episode with shock or life-threatening
  * Isolated pulmonary embolism with a systolic pulmonary artery pressure \> 60 mmHg at presentation
  * Deep vein thrombosis/ Pulmonary embolism associated with active cancer, antiphospholipid syndrome or long-standing medical illnesses
  * More than one idiopathic event
* Index venous thromboembolic event in different sites than deep veins of the lower limbs or pulmonary arteries

B) Exclusion criteria present at the moment of patients' screening:

* Age younger than 18 or older than 75 years
* More documented unprovoked venous thromboembolic episodes
* Pregnancy or puerperium
* Severe post-thrombotic syndrome (≥ 15 points at the Villalta score)
* Solid neoplasia or blood disease in active phase or requiring chemotherapy/radiotherapy
* All the clinical conditions requiring prolonged treatment with Low Molecular Weight Heparin
* Presence of overt, active chronic diseases (i.e. inflammatory bowel disease)
* Known serious thrombophilic alterations:

  * deficiencies of natural anticoagulants (Antithrombin, Protein C, Protein S)
  * homozygosity for Factor V Leiden or Factor II G20210A mutations
  * double heterozygosity
* Presence of antiphospholipid syndrome
* Presence of vein cava filter
* Concomitant conditions (such as atrial fibrillation) requiring indefinite anticoagulation
* Severe cardio-respiratory insufficiency (NYHA 3 or 4)
* Any absolute contraindications to anticoagulation treatment
* Any other contraindications to Apixaban as per local SmPC
* Life expectancy shorter than 1 year
* Refuse interruption of anticoagulation to perform serial D-dimer assessment
* Geographically inaccessible location
* Inability or refusal to give consent

Primary outcomes:
measure: Number and rate of patients with confirmed recurrent VTE and VTE-related death (efficacy).
timeFrame: From date of enrollment until the date of first documented event assessed up to 18 months
measure: Number and rate of major Bleeding events (defined according to International Society on Thrombosis and Haemostasis guidelines (safety)
timeFrame: From date of enrollment until the date of first documented event assessed up to18 months
Secondary outcomes:
measure: Number of and rate of thromboembolic events
timeFrame: From date of enrollment until the date of first documented event assessed up to 18 months
measure: Presence of severe post-thrombotic syndrome according to Villalta Score
timeFrame: 18 months
measure: Number and rate of non major bleeding complications
timeFrame: From date of enrollment until the date of first documented event assessed up to18 months
measure: Number and rate of dead patients (overall mortality)
timeFrame: From date of enrollment until the date of first documented event assessed up to 18 months
Other outcomes:
Locations:
city: Firenze
country: Italy
facility: Daniela Poli
Study officials:
affiliation: Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy
name: Daniela Poli, MD
role: STUDY_DIRECTOR
References:
citation: Palareti G, Poli D, Ageno W, Legnani C, Antonucci E, Bucherini E, Testa S, Paoletti O, Chistolini A, Serrao A, Martinelli I, Bucciarelli P, Falanga A, Tosetto A, Sarti L, Mastroiacovo D, Cosmi B, Visona A, Santoro RC, Zanatta N, Grandone E, Bertu L, Pengo V, Caiano L, Prandoni P. D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study. Blood Adv. 2022 Dec 13;6(23):6005-6015. doi: 10.1182/bloodadvances.2022007973.