Anticoagulation and/or Antiplatelet in Thrombotic Antiphospholipid Syndrome with Previous Arterial Thromboembolism: A Retrospective Cohort

Introduction: Thrombotic antiphospholipid syndrome (TAPS) is a prothrombotic autoimmune disease associated with a high risk of arterial thromboembolism (ATE). While direct oral anticoagulants (DOAC) are inferior treatment in TAPS with ATE, the optimal antithrombotic regimen of vitamin K antagonists (VKA) and/or antiplatelet therapy (AP) remains unclear.

Objectives: To assess the effectiveness and safety of VKA (target (t) international normalized ratio (INR) 2-3), VKA (t INR 2-3) with AP (including dual AP therapy), VKA (t INR >3), VKA (t INR >3) with AP, and AP alone at preventing recurrent thrombotic events in TAPS patients with previous ATE.

Methods: This retrospective cohort study included adult TAPS patients with previous ATE assessed at two academic tertiary care centers in Toronto, Canada between April 1, 2011 to April 1, 2021.

Included patients met Sydney criteria for TAPS and had a history of ATE (ischemic stroke (IS), transient ischemic attack (TIA), myocardial infarction (MI), or systemic embolism (SE)). At participating centers, patients with a thrombotic history suspicious for TAPS were screened for lupus anticoagulant, anti-cardiolipin antibodies, and/or anti-beta-2-glycoprotein 1 antibodies (anti-B2GP1) at the discretion of the treating physician. Testing for anti-B2GP1 was only available as a send away test. We excluded patients with a known cardioembolic source for their ATE including atrial fibrillation, patent foramen ovale, mechanical heart valves, Libman-Sacks endocarditis, those with initial ATE associated with catastrophic antiphospholipid syndrome (CAPS), and those treated with DOAC.

Outcomes included both thrombotic and bleeding events. Recurrent thrombosis included both ATE and VTE. ATE included IS, TIA, MI, or SE. Bleeding events were categorized as major bleeding (MB) or clinically relevant non-major bleeding (CRNMB) as defined by International Society on Thrombosis and Haemostasis criteria. Outcomes were assessed during the time the particular antithrombotic regimen was used. If a single patient had multiple antithrombotic regimens, they were included in multiple groups for the time they used that particular antithrombotic regimen, defined as antithrombotic trials.

Outcomes were calculated as the number of events per 100 patient years by antithrombotic regimen with 95% confidence intervals (CI) using Poisson's exact test. Statistical calculations were performed using SPSS.

Results: From an initial 891 patients with at least one positive antiphospholipid antibody test, 120 patients met criteria for TAPS and had a previous ATE. 62 patients were excluded for the following reasons: 47 for a cardio-embolic source of ATE, 5 for absence of any follow up, 7 for use of DOAC, and 3 for CAPS in the absence of any other ATE. After exclusions, 58 patients with a total of 89 antithrombotic trials were included in the analysis with a cumulative follow up of 248.4 years.

The study population comprised of thirty-one (53.4%) women with a mean age of 51 (Standard Deviation (SD) 12.9) years at the start of their initial antithrombotic trial. Twenty-three (39.7%) patients were known to have systemic lupus erythematosus (SLE) whereas seven (12.1%) patients had non-SLE autoimmune disorders. Thirty-four (58.6%) patients had baseline hypertension. The baseline characteristics are summarized in table 1.

Overall, there were a total of 7 ATE and 1 VTE recurrences with a thrombotic rate of 3.2 per 100 patient-years (95% CI 1.4 to 6.3). The recurrence rates in the VKA (t INR 2-3), VKA (t INR 2-3) with AP, VKA (t INR >3) with AP, and AP alone were 3.3 (95% CI 0.9 to 8.4), 2.6 (95% CI 0.3 to 9.3), 0 (95% CI 0 to 18.8), and 6.8 (0.8 to 24.4) per 100 patient-years respectively.

There were a total of 10 MB events including 4 intracranial bleeding (ICB), 1 gastrointestinal bleeding, and 5 other types of MB. ICB occurred in 3 patients on VKA (t INR 2-3) and 1 on VKA (t INR 2-3) with AP. Outcomes are summarized in table 2.

Conclusions: This retrospective cohort of 58 patients with TAPS and a previous ATE demonstrated a numerically higher risk of recurrent thrombosis with AP alone and a numerically higher risk of MB with the combination VKA and AP. Study limitations include the small sample size, risk of selection bias, and retrospective design. Larger, prospective studies are needed to confirm our observations.

No relevant conflicts of interest to declare.