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Drug Discoveries & Therapeutics. 2024; 18(4):213-219.

Review

DOI: 10.5582/ddt.2024.01050

Rethinking the use of direct oral anticoagulants for secondary
thromboprophylaxis in patients with thrombotic antiphospholipid
syndrome
Anabel Franco-Moreno1,*, Aida Izquierdo-Martínez2, Cristina Ancos-Aracil2
1
2

Department of Internal Medicine, Venous Thromboembolism Unit, Hospital Universitario Infanta Leonor, Madrid, Spain
Department of Internal Medicine, Venous Thromboembolism Unit, Hospital Universitario de Fuenlabrada, Madrid, Spain.

SUMMARY

Patients with thrombotic antiphospholipid syndrome (APS) are at high risk for recurrent thrombosis,
and indefinite anticoagulation is recommended. Patients with APS merit indefinite anticoagulation,and vitamin K antagonists (VKAs) have historically been the standard treatment. Direct oral
anticoagulants (DOACs) present an appealing alternative to VKAs. Due to their pharmacokinetic
and pharmacodynamic characteristics, DOACs offer advantages over VKAs, namely the lackof need for laboratory monitoring, the usage of a fixed dosage, and the absence of significant
interaction with dietary components and drugs. The efficacy and safety of DOACs in patients with
APS have been studied in four phase II/III clinical trials (three with rivaroxaban and one with
apixaban). These studies showed DOACs' inferiority compared to VKAs in preventing recurrent
thrombosis. Recurrence was significantly greater in patients with arterial thrombotic events and a
triple positivity for antiphospholipid antibodies. No differences were observed in the incidence ofvenous thromboembolism between both groups. Major bleeding was similar in patients treated with
DOACs or VKAs. Several observational studies have reported similar results. This review aims
to analyse the existing evidence on the efficacy and safety of DOACs for secondary prevention inpatients with APS.

Keywords

Antiphospholipid syndrome, arterial and venous thrombosis, bleeding, direct-acting oral
anticoagulants, secondary prevention, vitamin K antagonists

1. Introduction
Antiphospholipid syndrome (APS) is a complex
autoimmune disease characterised by arterial, venous,
or small vessel thrombosis in any tissue or organ thatcan present as obstetric morbidity. Meeting the clinicalcriteria previously mentioned and determining thepresence of antiphospholipid antibodies (APLAs) as
laboratory criteria is essential for diagnosis. APLAs
include lupus anticoagulant (LA) measured by functionalclotting assays, anticardiolipin antibody (aCL) andanti-β2 glycoprotein I (aβ2GPI) immunoglobulin (Ig)type G and/or type IgM assayed by solid phase enzymelinked immunosorbent assay (ELISA) at medium (40-70
GPL units) or high (≥ 80 GPL units) titres. Laboratory
testing must be positive on at least two separate occasions
12 weeks apart. New APS classification criteria haverecently been published jointly by The American Collegeof Rheumatology (ACR) and The European Alliance of

Associations for Rheumatology (EULAR) (1). The 2023
criteria are intended to be more specific than the Sydney
2006 criteria (2) to better identify patients with APS (99%and 86%, respectively).
APS management is based on long-term
anticoagulation due to the high risk of recurrent
thrombosis among non-treated patients (3,4). Patientswith APS should receive indefinite oral anticoagulation
with vitamin K antagonists (VKAs). In patients withvenous thrombosis the goal is to achieve and maintain an
International Normalised Ratio (INR) between 2-3 andin patients with arterial thrombosis to maintain an INRof 2-3 or 3-4, depending on the thrombotic and bleedingrisk. In case of recurrence despite an adequate INR in
both, arterial and venous thrombosis, the recommendation
is to maintain an INR of 3-4 or to add low doses ofacetylsalicylic acid (5).
Direct oral anticoagulants (DOACs) have shown asimilar, in some case even superior, efficacy and safety

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Drug Discoveries & Therapeutics. 2024; 18(4):213-219.
profile compared to VKAs in the treatment and secondary
prevention of venous thromboembolism (VTE) (6-8)
and in the prevention of stroke and systemic embolism
in patients with non-valvular atrial fibrillation (6,8-10).
However, controversy has arisen around the use of thesedrugs in APS. This study aims to review the currently
available literature to determine the efficacy and safetyof these drugs in secondary thromboprophylaxis in APS
to detect groups of patients who may benefit from thisantithrombotic therapy.
2. Evidence from clinical trials
Four randomized controlled trials (RCT) have been
conducted to evaluate the efficacy and safety of DOACs
in secondary prevention of patients with APS (Table
1) (11-14). These RCTs include RAPS (rivaroxaban
in antiphospholipid syndrome) (11), TRAPS (trial
on rivaroxaban in antiphospholipid syndrome) (12),rivaroxaban versus VKA in APS: a randomized noninferiority trial (13), and ASTRO-APS (apixaban forthe secondary prevention of thrombosis among patientswith antiphospholipid syndrome) (14). RCTs involved
474 patients, comprising 234 assigned to DOACs and
240 to VKAs. Studies were conducted in the United
Kingdom (11), Italy (12), Spain (13), and the UnitedStates (14). Women accounted for 70.8%, and 56% of
the participants had triple positive for APLAs. The meanfollow-up time was 18.8 months.
RAPS study, the first in this field, was a prospective,
open-label, non-inferiority clinical trial in patients with
APS and a history of VTE, whose main objective was todemonstrate the non-inferiority intensity anticoagulationachieved with rivaroxaban when compared to warfarin,
using endogenous thrombin measurement (11). One
hundred and sixteen patients treated with warfarin for atleast three months after the VTE event were included.
Although rivaroxaban did not meet the primary endpointof the study versus warfarin, no recurrent thrombotic
events were observed and both drugs were equally safein terms of major bleeding.
TRAPS (Trial on Rivaroxaban in AntiPhospholipid
Syndrome at high-risk for thromboembolic recurrence)
study was a prospective, randomized, non-inferiority trial
comparing the efficacy and safety of rivaroxaban versus
warfarin for the prevention of recurrent thrombotic
events, major bleeding and death from vascular cause
in patients with triple-positive APLAs (LA, aCL andaβ2GPI) (12). Patients were randomized to receive
rivaroxaban 20 mg/day or warfarin (target INR 2.5).
The trial was prematurely stopped by the adjudicationand safety committee for an excess of events in therivaroxaban group. At the time of trial termination, 120
patients had been randomized: 59 in the rivaroxabangroup and 61 in the warfarin group. Seven patients
experienced arterial events in the rivaroxaban arm,
whereas there were no cases of arterial thrombosis in the214

warfarin group. In the rivaroxaban arm, ischemic stroke
occurred in 4 (7%) patients, and myocardial infarction
occurred in 3 (5%) patients. No episode of VTE wasrecorded in either arm. There were 4 and 2 cases ofmajor bleeding in the rivaroxaban and warfarin groups,
respectively (hazard ratio [HR], 2.5; 95% confidence
interval [CI], 0.5-13.6; p = 0.3). The use of rivaroxaban
in patients with APS and triple-positive APLAs wereassociated with an increased rate of arterial thrombotic
events compared with warfarin.
A Spanish study evaluated the efficacy and safety ofrivaroxaban administered at doses of 20 mg or 15 mg
daily depending on renal function, compared with VKAs
in patients with thrombotic APS (13). After three years
of follow-up, recurrent thrombosis occurred in 11 of 95
patients (11.6%) treated with rivaroxaban and in 6 of 95(6.3%) treated with VKAs (relative risk [RR], 1.83; 95%
CI, 0.71-4.76; p = 0.21). Notably, 9 of the 11 recurrencesin the DOAC arm were strokes (81.8% vs. 0%; p < 0.001).
Rivaroxaban did not meet the specified criterion for noninferiority to VKAs. The incidence of major bleedingwas 6.3% (6/95) in the rivaroxaban group and 7.4% (7/95)
in the VKA group (RR 0.86; 95% CI, 0.30-2.46; p = 0.77).
In this study, rivaroxaban showed a near doubling of
the risk for recurrent thrombosis compared to VKAs forthrombotic APS.
More recently, in the ASTRO-APS study, 48 patientswith APS were randomised to receive apixaban 2.5
mg/12 h, apixaban 5 mg/12 h or warfarin (14). The
primary efficacy objective was the combined endpointof thrombosis (arterial and venous) and death fromvascular cause, and the primary safety objective wasmajor bleeding and clinically relevant minor bleeding.
The primary efficacy endpoint occurred in 6 of 23
patients (26%) treated with apixaban (3 in the 2.5 mggroup and 3 at the 5 mg dose). All were strokes. Noneof the patients randomised to warfarin had thrombotic
recurrence. The incidence of major bleeding was 4%(1/25) in the warfarin group with no events in apixabantreated patients. Apixaban showed inferiority compared
to warfarin in preventing recurrent thrombosis, especiallystrokes, among patients with APS.
3. Direct oral anticoagulants in secondary prevention
in arterial thrombosis in patients with antiphospholipid
syndrome
RCTs have consistently demonstrated a significantly
increased risk of subsequent arterial thrombosis inpatients treated with DOACs. The overall incidence of
new arterial thrombosis in the group treated with DOACs
was 10.3% versus 1.3% in those receiving VKAs (oddsratio [OR], 5.43; 95% CI, 1.87-15.75; p < 0.001) (15).
Compared with VKAs, rivaroxaban and apixaban showeda higher rate of stroke (8.6% versus 0%; OR, 10.74; 95%
CI, 2.29-50.38; p < 0.001). No differences were observed
for myocardial infarction (1.3% versus 0%; OR, 2.15;

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2018
Italy
Arterial and venous
20.4
Rivaroxaban 20 or 15 mg day/ Warfarin (INR 2.5)
59 / 6146.5 /46.1
66 /620/0
0/0
100 / 100Recurrent thrombosis
12% versus 0%
7% versus 3%, (p = 0.30)
Rivaroxaban was inferior to warfarin forprevention of recurrent thrombosis.

2016

United Kingdom

VTE

7

Rivaroxaban 20 mg day/ Warfarin (INR 2.5)

57 / 59

47 / 5074 / 71

60 / 48
28 / 32
12 / 20

Intensity of anticoagulation achieved bythrombin measurement

None for both groups

None for both groups

Rivaroxaban did not meet the primary
efficacy endpoint versus warfarin (endogenous
thrombin 1086 nmol/L per minute versus 548
nmol/L per minute, respectively; p < 0.0001);
however, no recurrent thrombotic events wereobserved.

Sample size

Mean age

Female gender, %APLAs profile, %SimpleDoubleTripleRecurrent thrombosis

Major bleeding

Study findings

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Rivaroxaban did not demonstrate noninferiority to VKAs. The recurrent
thrombosis rate was twice as high as with
VKAs.

6.3% versus 7.4%, (p = 0.77)

11.6% versus 6.3%, (p = 0.21)

Recurrent thrombosis

34 / 32
5/8
61 / 60

64 / 63

47* / 51*

95 / 95

Rivaroxaban 20 or 15 mg day/ VKA (INR 2-3)

36

Arterial and venous

Spain

2019

Ordi-Ros et al. (13)Apixaban was inferior to warfarin forprevention of recurrent thrombosis.

0% versus 4%

26% versus 0%

Combined endpoint for arterial and venous
thrombosis and death from vascular cause

22 / 28
17 / 830 / 28

83 / 84

46 / 48.5

23 / 25

Apixaban 5 or 2,5 mg/12 h/ Warfarin (INR 2-3)

12

Arterial and venous

United States

2022

ASTRO-APS (14)*Ordi-Ros et al. used median and interquartile range. Abbreviations: APLAs, antiphospholipid antibodies; DOACs, direct oral anticoagulants; VKAs, vitamin K antagonists; VTE, venous thromboembolism.

Efficacy primary endpoint

DOACs/comparison

Median follow-up in months

Initial thrombosis event

CountryYear

TRAPS (12)RAPS (11)Table 1. Results of clinical trials investigating the efficacy and safety of direct oral anticoagulants for secondary prevention of thrombosis in patients with thrombotic antiphospholipid
syndrome

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Drug Discoveries & Therapeutics. 2024; 18(4):213-219.
95% IC, 0.35-13.11; p = 0.41) or peripheral embolism(0.4% versus 1.3%; OR, 0.58; 95% CI, 0.12-2.92; p =0.51).
Observational cohorts comparing DOACs to VKAs
also show an increased incidence of arterial events inpatients treated with DOACs. In the study by Williams
et al., a nearly 3-fold increased risk of arterial recurrence
was observed with rivaroxaban, apixaban and edoxaban
compared to warfarin (16). This ratio was previously
detected with rivaroxaban in a prospective series (17).
Meta-analyses have reported a significantly increased
risk of new arterial thrombosis with DOACs compared
to VKAs. Except for the meta-analysis by SánchezRedondo et al. (18), a higher incidence of new arterial
events have been demonstrated in patients treatedwith DOACs with varying follow-up periods (6 to 72
months). Reviews by Wu et al. (OR, 2.27; 95% CI, 1.284.00; p < 0.005) (19), Gullapalli et al. (OR, 2.61; 95%
CI, 1.44-4.71; p < 0.001) (20) and Attachaipanich et al.
(OR, 4.06; 95% CI, 1.33-12.40) (21) consistently show
a significant increase in arterial recurrence in patientstreated with DOACs. Gullapalli et al. also analysed
the risk of recurrent arterial thrombosis in the patient
subgroup additionally receiving antiplatelet therapy. A
higher risk was reported in the DOACs arm, althoughstatistical significance was not reached (6.7% in the
DOACs arm versus 2.3% in the VKAs arm) (20).
4. Direct oral anticoagulants in secondary preventionof venous thromboembolism in patients with
antiphospholipid syndrome
Clinical trials found that the incidence of VTE was low
in individuals with APS treated with either DOACs or
VKAs (1 pulmonary embolism [PE] and 3 cases of deepvein thrombosis [DVT] with DOACs, and 3 events of
DVT with VKAs). No differences were observed in theincidence of VTE between both groups (1.7% versus
1.3%; OR, 1.20; 95% CI, 0.31-4.55; p = 0.79) (15). The
risk of PE (0.4% versus 0%; OR, 1.49; 95% IC, 0.23-9.53;
p = 0.68) and DVT (1.3% versus 1.3%; OR, 1.03; 95%
CI, 0.23-4.57; p = 0.97) was similar.
In observational studies that have compared DOACs
to VKAs, the results regarding the incidence of VTE areheterogeneous. Three cohorts’ studies (16,17,22) reporta similar incidence of VTE, a statement not corroborated
by Sato et al. (23). Notably, in this series two of the three
events were cerebral venous sinus thrombosis (CVST).
Several meta-analyses have demonstrated that theincidence of VTE among both treatments is similar. A
recent meta-analysis analysing 1,145 patients from 9
studies conclude that the incidence of VTE is similar
in individuals with APS treated with either DOACs or
warfarin (OR, 1.22; 95% CI, 0.68-2.17; p = 0.51) (19).
Another analysis pooling 12 studies with a total of 1,437
patients showed an incidence of venous thrombosis(DVT/PE/CVST) of 3.8% in patients treated with

216

DOACs and 2.6% in those treated with VKAs (OR, 1.17;
95% CI, 0.66-2.07; p = 0.60) (20).
5. Influence of immune phenotype on recurrent
thrombosis
APLAs profile has prognostic implications. Triple
positivity (AL, aCL and aβ2GPI) increases the risk ofrecurrent thrombosis. In a Chinese study of patients with
APS, the recurrence was significatively higher in triple
positive patients treated with DOACs versus VKAs (RR,
3.65; 95% CI, 1.49-8.93) (19). In the series by Dufrost
et al. involving 122 patients with APS, there was a clear
trend towards new thrombosis in triple-positive patientstreated with DOACs versus warfarin (OR, 3.69; 95%
CI, 1.12-12.14; p = 0.05) (24). In the meta-analysis by
Gullapalli et al. involving a total of 1,437 patients with
APS, the recurrence was significantly higher in the
triple positive DOACs arm (RR, 4.50; 95% CI, 1.9110.63; p = 0.0006) (20). In another recent meta-analysis
triple positivity was associated with a 4-fold increased
risk for thrombotic recurrence (25). A study comparing
the occurrence of new thrombosis with rivaroxaban,
apixaban and dabigatran versus VKAs showed asignificantly higher incidence of recurrence in triple
positive patients (56% versus 23%, respectively; OR, 4.3;
95% CI, 2.3-7.7; p < 0.0001) (26).
The results the regarding the recurrence ofthrombosis in patients with single/double positive
APLAs are controversial. In the previously mentioned
RAPS study, 85% of patients were single/double positive(11). The authors found no difference in the developmentof new thrombotic events between rivaroxaban andwarfarin in this subgroup of patients. The study by
Legault et al. analysed the safety of rivaroxaban (singlearm) in 82 patients with APS, none of whom were triple
positive. After a median follow-up of 19 months, four
recurrences were observed (two strokes and two VTE
events) (27). The authors conclude that the incidence ofrecurrent thrombosis is comparable to VKA treatment.
In a retrospective cohort of patients with APS treatedwith DOACs, the incidence of a new thrombosis was
1.7 events/year in triple positive patients compared to
0.7 for single/double-positive patients (RR 2.72; 95%
CI, 0.41-18.0) (28). More recently, a retrospective study
including 50 patients with non-triple positive APS and
VTE treated with DOACs observed a low incidence of
new thrombosis (0.64 events per 100 patients/year) (29).
In contrast, in other series no differences were observed
between single/double and triple positive groups,
although without reaching statistical significance (16,30).
6. Major bleeding as an adverse effect of anticoagulant
therapy
Anticoagulant therapy carries an increased risk of
bleeding complications. In this regard, DOACs

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Drug Discoveries & Therapeutics. 2024; 18(4):213-219.

Table 2. Clinical guideline recommendations for anticoagulation therapy in patients with thrombotic antiphospholipid
syndrome
Clinical Guidelines

Recommendation

European Alliance of Associations
for Rheumatology (EULEAR), 2019 (5)For patients with venous thrombosis, indefinite anticoagulation is recommended. DOACs may be analternative in patients unable to achieve target INR with VKAs, or intolerant to VKAs. Rivaroxaban
should not be used in triple positive patients due to the increased risk of recurrent thrombosis.
For arterial events, indefinite anticoagulation is also recommended, avoiding the use of DOACs.

European Society of Cardiology(ESC), 2019 (35)Indefinite treatment with VKAs is recommended. DOACs are not recommended.

American Society of Hematology(ASH), 2020 (36)

Indefinite anticoagulation with VKAs is recommended. The use of DOACs is discouraged.

British Society for Haematology(BSH), 2020 (37)

For patients with venous thrombosis, indefinite anticoagulation is recommended. DOACs should not
be used in triple-positive patients. Evidence is insufficient to establish recommendations in single or
double positive patients. In general, it is suggested to avoid them; however, if patients are already being
treated with DOACs, they may be continued depending on the clinical profile and patient preferences.
In patients with arterial thrombosis, indefinite treatment with VKAs is recommended. DOACs are notrecommended.

National Institute for Health andCare Excellence (NICE), 2020 (38)VKAs are recommended in triple positive patients.

International Society on Thrombosisand Haemostasis (ISTH), 2020 (39)

In patients with high-risk thrombotic APS*, VKAs are recommended. In patients with APS withouthigh-risk criteria who are already on DOACs therapy, it may be maintained depending on the clinicalprofile and patient preference.

American College of Cardiology(ACC), 2024 (40)

DOACs are not considered standard treatment in patients with APS.

*High-risk thrombotic APS is defined as meeting at least one of the following criteria according to the Sydney Convention (2006): a) triple positivity,b) arterial thrombosis, c) small vessel thrombosis with organ involvement, d) cardiac valvular heart disease. Abbreviations: APS, antiphospholipid
syndrome; APLAs, antiphospholipid antibodies; DOACs, direct oral anticoagulants; INR, international normalised ratio; VKAs, vitamin K
antagonists.

have proven superior to VKAs in patients with atrial
fibrillation, particularly in reducing the incidence of
intracranial haemorrhage by up to 50% (31-33).
In the four RCTs with DOACs, 20 major bleeding
events were reported, 10 in each treatment arm. Pooleddata showed no difference between therapy with DOACs
or VKAs (4.3% versus 4.2%; OR, 1.02; 95% CI, 0.4-2.47;
p = 0.97) (15). There was also no difference for clinically
relevant non-major bleeding (6.0% vs. 2.9%; OR, 1.90;
95% CI, 0.78-4.66; p = 0.16).
All meta-analyses show that the risk of bleeding
is similar in patients with APS treated with DOACs
or VKAs. The rates of major bleeding were 4.4% and4.2%, and the rates of clinically relevant non-major
bleeding were 5.6% and 5.5%, respectively, during amean follow-up period of 12-36 months (19,20,24-26,34).
The incidence of intracranial haemorrhage was also
equivalent for both groups (0.37% for DOACs and 0.42%
for VKAs).
7. Conclusion
In conclusion, patients with APS are at high risk ofrecurrent thrombosis; therefore, they require indefinite
anticoagulant therapy. Based on the outcomes of RCTs
with rivaroxaban and apixaban, DOACs are generally
not recommended (Table 2). Nevertheless, the outcomes

were poor in high-risk APS patients, including thosewith previous arterial thrombosis and triple positivity.
Furthermore, these studies were small and lacked
sufficient power to evaluate thrombotic outcomesrobustly. Currently, the clinical guidelines of EULAR(5), the British Society for Haematology (37) and theInternational Society on Thrombosis and Haemostasis(39) suggest that DOACs could be an alternative inpatients unable to achieve the INR target with VKA
drugs or who are intolerant to them, as well as in nonhigh-risk APS patients, including single- or doublepositive serology and prior venous thrombosis. In thesepatients, the use of DOACs appears reasonably safe.
We emphasize the need for ongoing research further
to optimize anticoagulant therapy for this challenging
patient population.
Funding: None.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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Received July 3, 2024; Revised August 10, 2024; Accepted
August 19, 2024.
*Address correspondence to:Anabel Franco-Moreno, Department of Internal Medicine,
Venous Thromboembolism Unit, Hospital Universitario Infanta
Leonor. Avenida Gran Via del Este, 80, 28031, Madrid, Spain.
E-mail: anaisabel.franco@salud.madrid.org
Released online in J-STAGE as advance publication August28, 2024.

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