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Apixaban for Extended Anticoagulation (APIDULCIS) (APIDULCIS)

Primary Purpose

Venous Thromboembolism, Anticoagulants

Status

Terminated

Phase

Phase 4

Locations

Italy

Study Type

Interventional

Intervention

Apixaban

About this trial

This is an interventional prevention trial for Venous Thromboembolism focused on measuring Venous thromboembolism, D-Dimer, Apixaban, Extended treatment

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Daniela Poli

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Positive D-Dimer

Negative D-Dimer

Arm Description

At the first positive D-dimer results (during anticoagulation or after its temporary withdrawal) the patients are invited to assume Eliquis (apixaban) 2.5 mg twice daily, and continue this therapy for the following 18 months.

Patients with persistently negative results at the four serial D-dimer measurements, stay definitively without anticoagulation and discouraged to resume any antithrombotic drug for secondary VTE prevention.

Outcomes

Primary Outcome Measures

Number and rate of patients with confirmed recurrent VTE and VTE-related death (efficacy).

The occurrence of proximal deep vein thrombosis with or without pulmonary embolism (new or recurrent episode) wil be recorded in all patients

Number and rate of major Bleeding events (defined according to International Society on Thrombosis and Haemostasis guidelines (safety)

Fatal bleeding; intracranial; intraspinal; intraocular; pericardial; intra-articular; intramuscular with compartment syndrome; retroperitoneal,; acute clinically overt bleeding will be recorded in all patients

Secondary Outcome Measures

Number of and rate of thromboembolic events

Transient ischemic attack (TIA), Stroke, Myocardial infarction will be recorded in all patients

Presence of severe post-thrombotic syndrome according to Villalta Score

Patient with deep vein thrombosis as index event will be evaluated, at the and of follow-up, applying Villalta score, commonly used to diagnose post-thrombotic syndrome in the subacute phase of thrombosis. The presence of venous ulcer of the leg or a score > of 15 points indicate the occurrence of severe post-thrombotic syndrome. The maximum score is 33. The score from 5 to 9 points indicate mild post-thrombotic syndrome and from 10 to 15 points indicate moderate post-thrombotic syndrome

Number and rate of non major bleeding complications

In all patients will be recorded any sign or symptom of hemorrhage that does not fit the criteria for the definition of major bleeding but does meet at least one of the following criteria: 1)requiring medical intervention by a healthcare professional; 2) leading to hospitalization or increased level of care;3) prompting a face to face evaluation

Number and rate of dead patients (overall mortality)

VTE-related death; cardiovascular related-death; bleeding-related death; death for: cancer, infectious disease and unknown cause; sudden death will be recorded in all patients

Full Information

NCT ID

NCT03678506

First Posted

September 8, 2018

Last Updated

February 22, 2023

Sponsor

Arianna Anticoagulazione Foundation

1. Study Identification

Unique Protocol Identification Number

NCT03678506

Brief Title

Apixaban for Extended Anticoagulation (APIDULCIS)

Acronym

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

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Terminated

Why Stopped

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)

Study Start Date

August 16, 2018 (Actual)

Primary Completion Date

September 1, 2021 (Actual)

Study Completion Date

January 31, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Arianna Anticoagulazione Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Venous Thromboembolism, Anticoagulants

Keywords

Venous thromboembolism, D-Dimer, Apixaban, Extended treatment

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

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.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

800 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Positive D-Dimer

Arm Type

Experimental

Arm Description

Arm Title

Negative D-Dimer

Arm Type

No Intervention

Arm Description

Intervention Type

Drug

Intervention Name(s)

Apixaban

Other Intervention Name(s)

Apixaban and positive d-dimer

Intervention Description

Apixaban 2.5 mg x 2 will be administered to patients with positive D-dimer results

Primary Outcome Measure Information:

Title

Number and rate of patients with confirmed recurrent VTE and VTE-related death (efficacy).

Description

The occurrence of proximal deep vein thrombosis with or without pulmonary embolism (new or recurrent episode) wil be recorded in all patients

Time Frame

From date of enrollment until the date of first documented event assessed up to 18 months

Title

Number and rate of major Bleeding events (defined according to International Society on Thrombosis and Haemostasis guidelines (safety)

Description

Time Frame

From date of enrollment until the date of first documented event assessed up to18 months

Secondary Outcome Measure Information:

Title

Number of and rate of thromboembolic events

Description

Transient ischemic attack (TIA), Stroke, Myocardial infarction will be recorded in all patients

Time Frame

From date of enrollment until the date of first documented event assessed up to 18 months

Title

Presence of severe post-thrombotic syndrome according to Villalta Score

Description

Time Frame

18 months

Title

Number and rate of non major bleeding complications

Description

Time Frame

From date of enrollment until the date of first documented event assessed up to18 months

Title

Number and rate of dead patients (overall mortality)

Description

VTE-related death; cardiovascular related-death; bleeding-related death; death for: cancer, infectious disease and unknown cause; sudden death will be recorded in all patients

Time Frame

From date of enrollment until the date of first documented event assessed up to 18 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniela Poli, MD

Organizational Affiliation

Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy

Official's Role

Study Director

Facility Information:

Facility Name

Daniela Poli

City

Firenze

ZIP/Postal Code

50134

Country

Italy

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

All collected data will be shared

IPD Sharing Time Frame

The data will be available after the publication of global results of the study or after 18 months from the enrollment of the last patients

IPD Sharing Access Criteria

Data access requests will be reviewed by the Scientific board of the study.

Citations:

PubMed Identifier

35914222

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.

Results Reference

derived

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Apixaban for Extended Anticoagulation (APIDULCIS)

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