Patient-level analysis of five international cohorts further confirms the efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies

Abstract

We performed an individual patient meta-analysis to determine whether aspirin has a significant protective effect on the risk of first thrombosis among patients with antiphospholipid antibodies (aPL). Five international cohort studies with available individual patient-level data, reporting on primary prophylaxis with continuous treatment with low-dose aspirin in patients with aPL were included. The main outcome was the occurrence of a first thrombotic in patients with aPL treated with low-dose aspirin compared to those not treated with low-dose aspirin. Pooled Hazard Ratios (HRs) and 95%CIs were calculated using frailty models. We pooled data from 497 subjects and 79 first thrombotic events (3469 patient-years of follow-up). After adjustment on cardiovascular risk factors, aPL profiles, and treatment with hydroxychloroquine, the HR for the risk of a first thrombosis of any type in aPL carriers treated with low-dose aspirin versus those not treated with aspirin was 0.43 (95%CI 0.25–0.75). Subgroup analysis showed a protective effect of aspirin against arterial (HR: 0.43 [95%CI: 0.20–0.93]) but not venous (HR: 0.49 [95%CI: 0.22–1.11]) thrombosis. Subgroup analysis according to underlying disease revealed a protective effect of aspirin against arterial thrombosis for systemic lupus erythematosus (SLE) (HR: 0.43 [95%CI: 0.20–0.94]) and asymptomatic aPL carriers (HR: 0.43 [95%CI 0.20–0.93]). We found no independent protective effect of hydroxychloroquine. This individual patient data meta-analysis shows that the risk of first thrombotic event as well of first arterial thrombotic event is significantly decreased among SLE patients and asymptomatic aPL individuals treated by low-dose aspirin.

Introduction

The adequate strategy for the primary prophylaxis of thrombosis in patients with antiphospholipid antibodies (aPL) remains very controversial [1], [2], [3], [4]. However, experts at the 13th International Congress on antiphospholipid antibodies have advocated the use of low-dose aspirin for primary prophylaxis of thrombosis in aPL carriers with high risk profiles such as lupus anticoagulant (LA) positivity or triple positivity (positivity of LA, anticardiolipin [aCL] and of anti-β2-glycoprotein-I [β2GPI] antibodies) or isolated persistently positive anticardiolipin antibodies aCL at medium-high titers [5]. Recently, we published a meta-analysis based on the literature [6], which revealed that patients treated with low-dose aspirin had an overall 2-fold reduction in the risk of a first thrombotic event compared to those not treated with aspirin. However, this finding was limited by the lack of adjustment on additional cardiovascular risk factors and the various proportions of patients with asymptomatic aPL, systemic lupus erythematosus (SLE) and obstetrical antiphospholipid syndrome (obsAPS) [7], [8] in each included study.

In the present study, we were able to further refine our previous findings. We performed an analysis of patient-level data from five international cohorts, to examine the effect of low-dose aspirin on the risk of first thrombotic event in patients with aPL, after adjustment on individual cardiovascular risk factors. Individual patient data meta-analysis is widely regarded as the gold standard, as it uses the ‘raw’ database obtained from each study to estimate an overall effect and not solely the global data extracted from each paper. In particular, a powerful and detailed analysis of treatment effect can be undertaken, including time-to-event analyses, in-depth data consistency checking, and more importantly adjustment on known confounding factors at the patient-level, to estimate how the characteristics of these patients modify treatment benefit. This study based on patient-level data therefore represents an important advance compared to our previous meta-analysis based on literature data.