Elsevier

Autoimmunity Reviews

Volume 17, Issue 10, October 2018, Pages 1011-1021
Autoimmunity Reviews

Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis

https://doi.org/10.1016/j.autrev.2018.04.009Get rights and content

Highlights

  • •

    Direct oral anticoagulants are not effective and safe in all APS patients.

  • •

    Triple positive patients have a four-fold increased risk of recurrent thrombosis.

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    Most recurrent thromboses occur within 12 months after DOACs initiation.

Abstract

Background

Direct oral anticoagulants (DOACs) are widely used for secondary prevention of venous thromboembolism (VTE) but their clinical efficacy and safety are not established in Antiphospholipid Syndrome (APS) patients. There is only one randomized controlled trial published while others are still ongoing. Many non-randomized studies have been published in this field with conflicting opinions.

Purpose of review

We conducted a systematic review using MEDLINE, EMBASE and Cochrane databases from 2000 until March 2018 regarding APS patients treated with DOACs. We performed a patient-level data meta-analysis to a) estimate the prevalence of recurrent thrombosis in APS patients treated with DOACs in the literature, and b) identify variables associated with recurrent thrombosis.

Results

We identified 47 studies corresponding to 447 APS patients treated with DOACs. Three commercially available DOACs were analyzed: rivaroxaban (n = 290), dabigatran etexilate (n = 144) and apixaban (n = 13). A total of 73 out of 447 patients (16%) experienced a recurrent thrombosis while on DOACs with a mean duration until thrombosis of 12.5 months. Rates of recurrent thromboses were 16.9% and 15% in APS patients receiving either anti-Xa inhibitors or dabigatran respectively. Triple positivity (positivity for all three antiphospholipid antibodies) was associated with a four-fold increased risk of recurrent thrombosis (56% vs 23%; OR = 4.3 [95%CI; 2.3–7.7], p < 0.0001) as well as a higher number of clinical criteria for APS classification. In patients treated with anti-Xa inhibitors, history of arterial thrombosis was associated with a higher risk of recurrent thrombosis (32% vs 14%; OR = 2.8 [95%CI; 1.4–5.7], p = 0.006).

In conclusion, DOACs are not effective in all APS patients and should not be used routinely in these patients. Randomized controlled trials assessing clinical efficacy and safety as primary endpoints are underway. In the meantime, a registry of APS patients on DOACs could be proposed to establish in which APS subgroups DOACs would be a safe alternative to warfarin.

Introduction

Definite antiphospholipid syndrome (APS) includes, according the Sapporo-Sydney criteria, at least one clinical criterion (arterial, venous or small vessel thrombosis or obstetrical morbidity) with positivity of at least one antiphospholipid antibody (aPL): lupus anticoagulant (LA), IgG or IgM anticardiolipin antibodies (aCL) and IgG or IgM anti-β2-glycoprotein-I (aβ2-GPI), detected on a minimum of two consecutive occasions at least 12 weeks apart [1]. APS can be primary or associated with an autoimmune disease, mainly systemic lupus erythematosus (SLE) [2]. All APS patients do not carry the same risk of thrombosis: those who are triple positive, i.e. for all three aPL tests have a higher risk for thrombosis, >5 events per 100 patient per year [3].

The cornerstone of APS patient management is secondary thromboprophylaxis with long-term warfarin treatment [4]. Four direct oral active anticoagulants (DOACs), rivaroxaban, apixaban, edoxaban, and dabigatran etexilate, are approved in the general population for secondary thromboprophylaxis after an episode of venous thromboembolism (VTE) [[5], [6], [7], [8]].

The use of DOACs in APS patients is controversial because of conflicting data from several case reports, case series, cross-sectional studies and one randomized controlled trial [9, 10].

We conducted a systematic review and patient-level data meta-analysis to estimate the rate of recurrent thrombosis in APS patients treated with DOACs and to identify risk factors predisposing to thrombotic events.

Section snippets

Meta-analysis protocol

Our study protocol was registered on PROSPERO (CRD42018084898). All stages of the conception of this meta-analysis were conducted according to PRISMA guidelines [11].

Search strategy

We conducted a systematic literature search in MEDLINE, EMBASE and Cochrane databases including all articles published from 2000 until March 15, 2018 reporting treatment with DOACs in APS patients. Reference lists of eligible studies and congress abstracts books were reviewed. Search terms (including MeSH terms) were:

Literature flow chart

The literature search identified 393 publications with either MEDLINE (n = 129), EMBASE (n = 261), conference abstracts (n = 2) or hand search (n = 1) from 1989 to 2018. Finally, 47 publications were included in the analysis (Fig. 1) including 447 patients.

Study characteristics

All articles included were published between 2014 and 2018. There were four randomized controlled trials (Rivaroxaban in APS (RAPS) study and patients from RE-COVER, RE-COVER II and RE-MEDY studies) [12, 13], 14 case series [[14], [15], [16],

Discussion

This international patient-level data meta-analysis of >440 APS patients with history of thrombosis showed that 16% of APS patients treated with DOACs developed a recurrent thrombosis; of note frequency of recurrent thrombosis was 33% in triple aPL-positive patients. Indeed, these high-risk patients had a dramatic 4-fold increased risk of thrombosis on DOACs compared with other APS patients.. Among triple positive APS patients treated with warfarin, recurrent thrombosis rate may reach 30%

Conclusion

This systematic review with patient-level data meta-analysis summarizes the existing evidence on APS patients treated with DOACs to date. Our results suggest a higher thrombotic risk in some APS patients treated with DOACs, especially those with a) a high-risk laboratory profile (triple positivity), b) a higher number of criteria for definite APS and c) previous arterial and small vessel manifestations. Furthermore, even in low-risk APS patients with a history of a single VTE, recurrent

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

None

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