Clinical trial NCT06884384: DOAC Versus VKA in Patients With Non-high-risk APS : Prospective Cohort Study
Official title: Direct Oral Anticoagulants Versus Warfarin in Patients With Non-high-risk Antiphospholipid Syndrome : Prospective Cohort Study
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Antiphospholipid Syndrome (APS)
Cohort Study
Thrombotic and Bleeding Events
Keywords: Antiphospholipid Syndrome
VKA treatment
DOAC Treatment
biological analysis
Thrombotic and bleeding events
Lead sponsor: Central Hospital, Nancy, France
Sponsor class: OTHER
First posted: 2025-03-19
Enrollment: 310
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Population of "non-high-risk" thrombotic APS patients treated with oral AntiXa or VKA regarding the treatment already taken at inclusion. Non-high-risk" APS is defined by no history of arterial or small vessels thrombosis, any valvulopathy related to APS, and a biological profile with only one or two positive antiphospholipid tests.

Patients will be recruited via the departments authorized to manage them, during their consultation or hospitalization. Patients will be invited to participate in the study as part of their regular follow-up visit. There will be no change in current antithrombotic treatment at the time of inclusion.

Brief summary: Antiphospholipid syndrome (APS) is a thrombotic disease requiring prolonged anticoagulation. Direct oral anticoagulants (DOACs) are indicated as 1st-line therapy in venous thrombosis, compared with VKAs, due to their easier handling and lower bleeding risk for equivalent efficacy. In APS, VKAs are still the reference treatment. However, DOACs are generally introduced in the acute phase of venous, before the diagnosis of APS. VKA have the disadvantage of numerous food and drug interactions, and therefore require close monitoring of INR, at least once a month. Because they are easier to use than VKAs, and the risk of bleeding is lower, patients are often reluctant to switch from DOACs to VKA. Studies have shown that APS patients with high thrombotic risk (positivity of all three antiphospholipid tests, history of arterial or small vessels thrombosis or cardiac valve damage) have an increased thrombotic risk during DOACs vs. VKA treatment. Since 2020, the ISTH guidelines have suggested avoiding DOACs in high-risk APS, but suggest continuing theim in other patients if they were introduced for venous thrombosis and if follow-up on DOACs is reassuring. In the case of high-risk APS patients, the relay is therefore systematic. For non-high-risk patients (the majority), there are no data to justify systematic switch. Given the quality-of-life advantages of DOACs over VKAs, patients are not always in favor of changing their anticoagulant therapy, especially if they have been on it for many years with good tolerability. For these reasons, a number of patients with non-high-risk APS remain on DOACs. Nevertheless, the limited data available on the efficacy of DOACs in non-high-risk patients are of low level of evidence and contradictory. In 2020, a literature review of non-high-risk SAPL patients treated with DOACs reported that 8.6% of them experienced thrombotic recurrence within 12 months, with no possible comparison with VKAs. A recent retrospective study with 96 patients reported that 15.4% of patients treated with DOACs had a recurrence, compared to 5.3% on VKAs. However, this difference was not statistically significant (p=0.15) due to a clear lack of power. The objective is to determine the frequency of thrombotic recurrences and to compare it according to the type of oral treatment, anti-Xa versus VKA, in non-high-risk APS, through a cohort study with prospective follow-up. The patient's usual antithrombotic treatment, DOAC and VKA, will be continued unchanged.

Detailed description: prospective cohort of APS patient treated with VKA or DOACs (specially oral Xa treatment).

APS patients will be non high risk patients (no triple positivity, any previous arterial or small vessels thrombosis or cardiac involvment).

the treatment taken by the patient at inclusion will not be modified. There will therefore be no change to the patient's usual management.

all patients will have a blood sample taken at inclusion as part of a routine blood test.

Patients will be prospectively follow up and the level of recurrence thrombotic event will be recorded

Eligibility criteria: Inclusion Criteria:

* Persons who have received full information about the organization of the research and have given their oral consent to participate.
* Male or female 18 years of age or older;
* Carrier of venous thrombotic SAPL:

  * Not favoured by a major or ≥ 2 minor favouring factors, if the patient doesn't present with obstetrical SAPL in accordance with the ACR/EULAR 2023 clinical classification criteria.
  * Or favored by ≥ 2 minors, if the patient has obstetrical SAPL: severe preeclampsia \< 34 weeks or placental insufficiency
  * Regardless of how long the disease has been present
  * With persistent positivity of at least one biological criterion:

    * Positivity of circulating lupus anticoagulant or IgG anticardiolipid or IgG anti-beta-2GPI
    * And persistence of the same positive test ≥ 12 weeks apart
    * And With maximum delay of positivity of the 1st antiphospholipid test of 3 years after the thrombotic event
* Current anticoagulant treatment, regardless of date of introduction

  * rivaroxaban or apixaban
  * or antivitamin K
* Patient affiliated to a social security system

Exclusion Criteria:

* Venous thrombotic event motivating current anticoagulant treatment favoured by a major favouring factor:

  * Active cancer
  * Hospitalization with bed rest for at least 3 days in the 3 months preceding the event
  * Major trauma with fractures or spinal cord injury in the month preceding the event
  * Surgery with general/spinal/epidural anesthesia for \> 30 minutes in the 3 months preceding the event.
* In the absence of a history of pre-eclampsia or placental insufficiency: venous thrombotic event motivating current anticoagulant treatment favoured by 2 or more minor favouring factors:

  * Systemic autoimmune disease or active inflammatory bowel disease
  * Acute/severe infection
  * Central venous catheter in the same vascular bed
  * Hormone replacement therapy, estrogenic oral contraceptives, or hormone-stimulating therapy in progress
  * Long-distance travel (≥ 8 hours)
  * Obesity (BMI ≥ 30 kg/m²)
  * Pregnancy or post-partum (6 weeks after delivery)
  * Prolonged immobilization
  * Surgery with general/spinal/epidural anesthesia for \< 30 minutes in the 3 months preceding the event
* Known triple antiphospholipid positivity
* Isolated IgM antiphospholipid positivity
* History of known arterial thrombosis
* History of known microcirculatory thrombosis
* Known SAPL-related cardiac valvular disease
* Persons referred to in articles L. 1121-5, L. 1121-7 and L1121-8 of the Public Health Code
* Persons deprived of their liberty by judicial or administrative decision, persons under psychiatric care under articles L. 3212-1 and L. 3213-1.
* Glomerular filtration rate \< 30ml/min.
* Weight \< 50kg
* History of thrombotic recurrence under well-administered anticoagulant therapy.

Primary outcomes:
measure: Frequency of thrombotic recurrence between the 2 arms
timeFrame: "From enrollment to the thrombotic recurrence or the end of the study (24 months post-inclusion)
Secondary outcomes:
measure: Risk Factors of thrombotic recurrence on the 2 arms
timeFrame: Biological parameters : at the end of the study after the last visit of the last patient. No biological parameters : from enrollment to the end of follow-up (24 months post-inclusion or thrombotic recurrence)
measure: Occurrence of major hemorrhage between the 2 arms
timeFrame: From enrollment to the end of follow-up (24 month post-inclusion or thrombotic recurrence)
measure: Occurrence of clinically relevant hemorrhage between the 2 arms
timeFrame: From enrollment to the end of follow-up (24 months post-inclusion or thrombotic recurrence)
measure: Occurrence of a minor bleed between the 2 arms
timeFrame: From enrollment to the end of follow-up (24 months post-inclusion or thrombotic recurrence)
measure: Net clinical benefit defined as a composite endpoint between the 2 arms
timeFrame: From enrollment to the end of follow-up (24 months post-inclusion or thrombotic recurrence)
measure: Drug Compliance evaluation between the 2 arms
timeFrame: From enrollment to the end of follow-up (24 months post-inclusion or thrombotic recurrence)
measure: Quality of life under anticoagulants evaluation by Anti-Clot Treatment Scale (ACTS) satisfaction scores between the 2 arms
timeFrame: From enrollment to the end of follow-up (24 months post-inclusion or thrombotic recurrence)
Other outcomes:
Locations:
city: Vandoeuvre-lès-Nancy
country: France
facility: Central Hospital, Nancy, France
state: Grand Est
city: Amiens
country: France
facility: CHU d'Amiens
city: Besançon
country: France
facility: CHU de Besançon
city: Brest
country: France
facility: CHU de Brest
city: Dijon
country: France
facility: CHU de Dijon
city: Lyon
country: France
facility: CHU de Lyon
city: Metz
country: France
facility: Hôpital Robert Schuman, UNEOS
city: Mulhouse
country: France
facility: CH de Mulhouse
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hôpital Lariboisière - APHP
city: Reims
country: France
facility: CHU de Reims
city: Saint-Priest En Jarez
country: France
facility: CHU de Saint Etienne
city: Strasbourg
country: France
facility: CHU de Strasbourg - Hôpital civil
Study officials:
affiliation: CHRU - Nancy
name: Virginie DUFROST, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Williams B, Saseen JJ, Trujillo T, Palkimas S. Direct oral anticoagulants versus warfarin in patients with single or double antibody-positive antiphospholipid syndrome. J Thromb Thrombolysis. 2022 Jul;54(1):67-73. doi: 10.1007/s11239-021-02587-0. Epub 2021 Nov 24.
citation: Dufrost V, Darnige L, Reshetnyak T, Vorobyeva M, Jiang X, Yan XX, Gerotziafas G, Jing ZC, Elalamy I, Wahl D, Zuily S. New Insights into the Use of Direct Oral Anticoagulants in Non-high Risk Thrombotic APS Patients: Literature Review and Subgroup Analysis from a Meta-analysis. Curr Rheumatol Rep. 2020 May 20;22(7):25. doi: 10.1007/s11926-020-00901-y.
citation: Zuily S, Cohen H, Isenberg D, Woller SC, Crowther M, Dufrost V, Wahl D, Dore CJ, Cuker A, Carrier M, Pengo V, Devreese KMJ. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: Guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2020 Sep;18(9):2126-2137. doi: 10.1111/jth.14935.
citation: Dufrost V, Risse J, Reshetnyak T, Satybaldyeva M, Du Y, Yan XX, Salta S, Gerotziafas G, Jing ZC, Elalamy I, Wahl D, Zuily S. Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis. Autoimmun Rev. 2018 Oct;17(10):1011-1021. doi: 10.1016/j.autrev.2018.04.009. Epub 2018 Aug 11.
citation: Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. doi: 10.1182/blood-2018-04-848333. Epub 2018 Jul 12.